KR20230112605A - Kinase Inhibitors and Uses Thereof - Google Patents

Abstract

Cyclic iminopyridine compounds and bicyclic derivatives thereof, pharmaceutical compositions comprising such compounds, and methods of using such compounds or compositions, for example, for the treatment of proliferative disorders such as cancer or tumors, or in some embodiments, diseases or disorders associated with dysregulation of kinases such as MAPK, PDGFR, Src, PAKs, c-Kit, EphA2, EphB4, FGFR, Axl and c-Met.

Description

Kinase Inhibitors and Uses Thereof

CROSS REFERENCES OF RELATED APPLICATIONS

[0001] This application claims priority based on US Provisional Application No. 63/063,113 filed on August 7, 2020, the contents of which are incorporated herein by reference in their entirety.

Field

[0002] The present disclosure relates to compounds, pharmaceutical compositions comprising such compounds, and the use of such compounds or compositions in methods or medicaments for the treatment of proliferative disorders, cancers or tumors, or in some embodiments, diseases or disorders associated with dysregulation of kinases such as, but not limited to, MAPK, PDGFR, Src, PAKs, c-Kit, EphA2, EphB4, FGFR, Axl, and c-Met kinases.

[0003] The present disclosure relates to the treatment of abnormal cell growth, such as cancer, more specifically brain cancer, in mammals, particularly humans, with the novel cyclic iminopyrimidines and bicyclic compounds thereof, and isotopic derivatives thereof, as disclosed herein, as well as pharmaceutical compositions containing such compounds. The present invention also relates to methods of preparing such compounds.

[0004] A kinase is an enzyme that catalyzes the transfer of a phosphate group from a high-energy phosphate donor molecule to a specific substrate. This process is known as phosphorylation, in which a substrate acquires a phosphate group and a high-energy ATP molecule donates a phosphate group. This transesterification reaction produces a phosphorylated substrate and ADP.

[0005] Kinases are classified into broad groups such as protein kinases, lipid kinases, and carbohydrate kinases according to the substrates on which they act. Kinases can be found in a variety of species, from bacteria to fungi, worms and mammals. Over 500 different kinases have been identified in humans.

[0006] MAP kinases (MAPKs) are a family of serine/threonine kinases that respond to a variety of extracellular growth signals. For example, growth hormone, epidermal growth factor, platelet-derived growth factor and insulin are all considered mitogenic stimuli that may be involved in the MAPK pathway. Activation of this pathway at the receptor level initiates a signaling cascade in which Ras GTPase exchanges GDP for GTP. Next, Ras activates Raf kinase (also known as MAPKKK), which activates MEK (MAPKK). MEK activates MAPK (also called ERK), which can regulate transcription and translation. Both RAF and MAPK are serine/threonine kinases, whereas MAPKK is a tyrosine/threonine kinase.

[0007] The oncogenic potential of the MAPK pathway makes it clinically important. It is associated with cellular processes that can lead to uncontrolled growth and subsequent tumor formation. Mutations in this pathway alter the regulatory effects on cell differentiation, proliferation, survival and apoptosis associated with various forms of cancer.

[0008] These kinases are known to be frequently and abnormally expressed in common human cancers such as melanoma, colorectal cancer, thyroid cancer, glioma, breast cancer and lung cancer. B-Raf, which also possesses kinase activity, has been shown to be mutated and/or overactive in many human cancers, such as brain, lung, melanoma, colorectal, ovarian and papillary thyroid carcinomas.

[0009] Inhibition of kinases is a useful method for treating certain types of cancer by inhibiting the growth of mammalian cancer cells. Various compounds such as pyrrolopyridine and anilinopyrimidine derivatives have been shown to have kinase inhibitory properties. A number of patent publications mention certain bicyclic derivatives, particularly quinazolinone derivatives.

[0010] Several compounds with various chemical structures have been developed as EphA2, Src and PAKs inhibitors, two of which (FRAX486 and G-5555) have been described as potent PAK1 inhibitors. For example, FRAX486 inhibits the PAK1 enzyme in the low nanomolar range.

[0011] However, due to their structural properties, many of these kinase inhibitors have poor pharmacokinetic properties, and some are substrates of active transporters such as P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP), and have a very low propensity to penetrate cell membranes as well as the brain. Therefore, it is not suitable for use in the treatment of tumors or cancer of the brain protected by the blood-brain barrier (BBB).

[0012] Accordingly, compounds of the present disclosure that are selective inhibitors of specific kinases are useful in the treatment of abnormal cell growth, particularly cancer in mammals. In addition, these compounds are useful for treating cancer including human tumors or brain tumors because of their good penetrability into cell membranes.

outline

[0013] In one aspect, a compound of formula (I):

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein:

G ¹ is N or CR ^a ;

G ² is N or CR ^b ;

n is 1 or 2;

m is 0, 1, 2 or 3;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ alkylamino, and optionally substituted aryloxy;

each R ¹ is independently selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;

or two R ¹ groups together with the carbon atoms to which they are connected form a 4- to 7-membered carbocyclic or heterocyclic ring optionally substituted by one or more R ^a groups;

R²is hydrogen, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆Alkyl-O, optionally substituted C_One-C₆Alkyl-S, optionally substituted C_One-C₆Alkyl-SO₂, optionally substituted C_One-C₆Alkyl-NR^a, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆Alkynyl, optionally substituted aryl, optionally substituted aryl-O, optionally substituted aryl-S, optionally substituted aryl-SO₂, optionally substituted aryl-NR^a, optionally substituted heteroaryl, optionally substituted heteroaryl-O, optionally substituted heteroaryl-S, optionally substituted heteroaryl-SO₂, optionally substituted heteroaryl-NR^a, optionally substituted cycloalkyl, optionally substituted cycloalkyl-O, optionally substituted cycloalkyl-S, optionally substituted cycloalkyl-SO₂, optionally substituted cycloalkylNR^a, optionally substituted heterocyclyl, optionally substituted heterocyclyl-O, optionally substituted heterocyclyl-S, optionally substituted heterocyclyl-SO₂, and optionally substituted heterocyclyl-NR^aIt is selected from the group consisting of;

R ³ is selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;

R ⁴ is selected from the group consisting of:

(i) hydrogen;

(ii) C ₁ -C ₆ alkyl optionally substituted with one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, hydroxyl, heteroaryl, and optionally substituted heterocyclyl;

(iii) heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, acryloyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted C ₁ -C ₆ alkyl-NR ^a , and optionally substituted heterocyclyl;

(iv) aryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -C(O)O(C ₁ -C- ₆ alkyl), acryloylamino, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C 1 -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted C _{1 -C 6} alkyl-NR ^a , and optionally substituted heterocyclyl;

(v) heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted C ₁ -C ₆ alkyl-NR ^a , optionally substituted heteroaryl, and optionally substituted heterocyclyl;

(vi) carbonyl substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -NRa(C ₁ -C ₆ alkoxy), and optionally substituted heteroaryl; and

(vii) —SO ₂ (C ₁ -C ₆ alkyl);

R ⁵ is hydrogen, C ₁ -C ₆ alkyl, or heterocyclyl;

or R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

provided that R ² is 2,6-dichloro-3,5-dimethoxyphenyl:

R ⁴ is selected from the group consisting of:

(i) hydrogen;

(ii) C ₁ -C ₆ alkyl optionally substituted with one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, hydroxyl, heteroaryl, and optionally substituted heterocyclyl;

(iii) heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, acryloyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(iv) aryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -C(O)O(C ₁ -C- ₆ alkyl), optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(v) heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

(vi) carbonyl substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -NRa(C ₁ -C ₆ alkoxy), and optionally substituted heteroaryl; and

(vii) —SO ₂ (C ₁ -C ₆ alkyl);

R ⁵ is hydrogen, C ₁ -C ₆ alkyl, or heterocyclyl;

or R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

[0014] In another aspect, a compound of formula (I-1a),

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, and n are as defined in formula (I).

[0015] In another aspect, a compound of Formula (I-2a) or (I-2b):

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and m are as defined in formula (I).

[0016] In another aspect, a compound of formula (I-3a) or (I-3b):

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein R ² , R ³ , R ⁴ , and R ⁵ are as defined in formula (I).

[0017] In some embodiments, a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, is provided.

[0018] In some aspects, provided is a pharmaceutical composition comprising a compound of any formula described herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, and a pharmaceutically acceptable diluent or carrier.

[0019] In some aspects, a combination containing at least one compound of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate or isotope derivative thereof, and a second prophylactic or therapeutic agent is provided.

In some aspects, a compound of Formula (I), such as a compound of Formula (I-1a), (I-2a), (I-2b), (I-3a), (I-3b), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, is provided for use in treating and/or preventing a proliferative disorder such as cancer or a tumor in a subject. In some embodiments, the proliferative disorder or cancer is selected from the group consisting of a malignant or benign tumor of the liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, liver carcinoma, sarcoma, glioblastoma, head and neck, melanoma, benign hyperplasia of the skin and other hyperplastic conditions such as benign hyperplasia of the prostate.

[0021] In some aspects there is provided a method of treating and/or preventing a proliferative disorder such as cancer or tumor in a subject, wherein the method comprises administering to the subject an effective amount of a compound of any formula provided herein, a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any formula disclosed herein, or a combination containing a compound of any formula disclosed herein. In some embodiments, the proliferative disorder or cancer is selected from the group consisting of liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, liver carcinoma, sarcoma, glioblastoma, malignant or benign tumor of the head and neck, melanoma, and benign hyperplasia of the skin and benign hyperplasia of the prostate.

[0022] In some aspects, the present disclosure provides the use of one or more compounds of any of the formulas described herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, for the manufacture of a medicament.

[0023] In some aspects, the present disclosure relates to MAPK, PDGFR, Src, PAKs, c-Kit, EphA2, EphB4, FGFR, Axl, and c-Met, comprising administering to a subject an effective amount of a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any formula disclosed herein, or a combination containing a compound of any formula disclosed herein. Provided are methods of producing an antiproliferative or antimetastatic effect in a subject having a proliferative disorder, cancer or tumor that is susceptible to inhibition of the same related kinase.

[0024] In some aspects, there is provided a compound of Formula (I), such as a compound of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, for use in the treatment of a neurodegenerative disease. In some embodiments, the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease.

[0025] In some aspects, the present disclosure provides methods of treating a neurodegenerative disease in a subject. In some embodiments, the method comprises administering to a subject an effective amount of a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any formula disclosed herein, or a combination containing a compound of any formula disclosed herein. In some embodiments, the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease.

[0026] In another aspect, one or more kinases, such as MAPK, PDGFR, Src, PAKs, c-Kit, EphA2, EphB4, FGFR, Axl, and, Methods of inhibiting the activity of c-Met are provided, wherein the contacting is in vitro, ex vivo or in vivo.

details

Justice

[0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications mentioned herein are incorporated by reference in their entirety. To the extent any definitions set forth in this section conflict with or are otherwise inconsistent with any definitions set forth in a patent, application, or other publication incorporated herein by reference, the definitions set forth in this section shall prevail over any definitions incorporated herein by reference.

As used herein, “a” or “an” means “at least one” or “one or more”.

[0029] As used herein, reference to "about" in reference to a value or parameter herein includes (and describes) embodiments relating to the value or parameter itself. For example, a description of "about X" includes a description of "X" itself.

[0030] Unless otherwise specified, as used herein, “individual” or “subject” refers to mammals, including but not limited to humans, bovines, primates, equines, dogs, cats, pigs, and ovine animals. Accordingly, the compositions and methods provided herein find use in both human medicine and veterinary contexts, including use in agricultural animals and pets. The subject can be a human diagnosed with or suspected of a condition described herein, such as cancer. The subject can be a human who exhibits one or more symptoms associated with a condition described herein, such as cancer. The subject can be a human with a mutant or abnormal gene associated with a condition described herein, such as cancer. The individual may be a human who is genetically or predisposed to or at risk of developing a condition described herein, such as cancer.

[0031] "Treatment" or "treating" as used herein is an approach for obtaining beneficial or desired results, including clinical results. For purposes of the compositions and methods provided herein, beneficial or desired clinical results include, but are not limited to, one or more of the following: reduction of one or more symptoms of a condition, reduction of severity of a condition, stabilization of a condition (e.g., avoidance of worsening of a condition). or delay), prevent or delay the spread of the condition (eg, metastasis), delay or slow the progression of the condition, ameliorate the condition of the disease, provide remission (partial or total) treatment of the disease, reduce the dose of one or more other drugs required to treat the condition; Improving the effectiveness of other drugs used to treat the condition, improving the quality of life and/or prolonging survival of individuals with the condition. Methods of treating cancer include reducing the pathological consequences of cancer. The methods described herein contemplate any one or more of these therapeutic aspects.

[0032] As used herein, an individual "at risk" is an individual at risk of developing a disease or condition described herein, such as cancer. An individual “at risk” may or may not have detectable disease, and may or may not have exhibited detectable disease prior to the treatment methods described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition described herein, such as cancer. Individuals with one or more of these risk factors are more likely to develop a disease or condition than individuals without these risk factor(s).

[0033] As used herein, "combination therapy" refers to therapy involving two or more different compounds. Accordingly, in one aspect, a combination therapy comprising a compound described herein and another compound is provided. In some variations, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds and/or inactive substances. In various embodiments, treatment with combination therapy can result in additive or even synergistic (eg, greater than additive) results compared to administration of a single compound provided herein alone. In some embodiments, lower amounts of each compound are used as part of a combination therapy compared to amounts normally used for individual therapy. Preferably, the same or greater therapeutic benefit is achieved using the combination therapy than using any individual compound alone. In some embodiments, the same or greater therapeutic benefit is achieved using smaller amounts (eg, lower doses or less frequent dosing schedules) of the compounds in combination therapy than the amounts normally used for the individual compounds or therapies. Preferably, the use of small amounts of the compound reduces the number, severity, frequency and/or duration of one or more side effects associated with the compound.

[0034] As used herein, the term "effective amount" refers to that amount of a compound provided herein that should be effective in a given therapeutic form in combination with parameters of efficacy and toxicity. As is understood in the art, an effective amount may be more than one dose, ie a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to provide an effective amount if a desired or beneficial result can be achieved or is achieved with one or more other agents. Appropriate dosages of any compounds administered concomitantly may optionally be lowered due to the combined action of the compounds (eg additive or synergistic effects). In various embodiments, an effective amount of a composition or therapy (i) reduces the number of cancer cells; (ii) reduce tumor size; (iii) inhibits, retards, slows, and preferably stops cancer cell infiltration into peripheral organs to some extent; (iv) inhibit (eg, slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay development and/or recurrence of tumors; and/or (vii) alleviate to some extent one or more symptoms associated with cancer. In various embodiments, the amount is an amount sufficient to ameliorate, alleviate, alleviate and/or delay one or more symptoms of a disease or condition described herein, such as cancer.

[0035] As is understood in the art, an "effective amount" may be more than one dose, i.e., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. An effective amount can be considered in the context of administering one or more therapeutic agents, compounds, or pharmaceutically acceptable salts thereof, and can be considered given in an effective amount if, when used in combination with one or more other agents, a desired or beneficial result can or is achieved.

[0036] "Therapeutically effective amount" means an amount of a compound or salt thereof sufficient to produce a desired therapeutic result (e.g., a result of reducing the severity or duration, stabilizing the severity, or eliminating a symptom of one or more symptoms of a disease or condition described herein, such as cancer). For therapeutic use, beneficial or desired results include, for example, reduction of one or more symptoms due to a disease (biochemical, histological, and/or behavioral), including intervening pathological phenotypes and complications present during development of the disease or condition, increasing the quality of life of those suffering from the disease or condition, reducing the dose of other drugs required to treat the disease or condition, improving the effectiveness of other drugs, delaying the progression of the disease or condition, and/or prolonging patient survival.

[0037] It is understood that an effective amount of a compound or a pharmaceutically acceptable salt thereof, including a prophylactically effective amount, can be given to a subject in an adjuvant setting, where the subject has a history of cancer and usually (but not necessarily) has responded to therapy, including but not limited to surgery (e.g., surgical resection), radiation therapy, and chemotherapy. However, because of their history of cancer, these individuals are considered to be at risk of developing cancer. Treatment or administration in an “adjuvant setting” refers to a subsequent treatment modality.

[0038] As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" means a biologically or otherwise undesirable material, e.g., such material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological side effects or without interacting in a detrimental manner with any other component of the composition containing such material. A pharmaceutically acceptable carrier or excipient preferably meets the requirements of toxicological and manufacturing testing and/or is included in the Inactive Ingredient Guide prepared by the US Food and Drug Administration.

[0039] A "pharmaceutically acceptable salt" is a salt that retains at least a portion of the biological activity of the free compound (but not a salt) and can be administered as a drug or medicament to an individual. Such salts are, for example, (1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or acid addition salts formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion or aluminum ion; or coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like. Pharmaceutically acceptable salts may be prepared in situ in the manufacturing process or may be prepared by separately reacting a purified compound provided herein in free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.

[0040] As used herein, the term "excipient" refers to an inactive or inactive substance that can be used in the manufacture of drugs or medicaments such as tablets containing a compound provided herein as an active ingredient. A variety of substances may be included within the term excipient, including but not limited to, any substance used as a binder, disintegrant, coating agent, compression/encapsulation aid, cream or lotion, lubricant, parenteral administration solution, chewable tablet material, sweetener or flavoring agent, suspending/gelling agent, or wet granulation agent. binders include, for example, carbomer, povidone, xanthan gum, and the like; coatings include, for example, cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrins, enteric coatings, and the like; compression/encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "direct compressible"), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose or microcrystalline cellulose), starch dc, sucrose, and the like; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, and the like; creams or lotions contain, for example, maltodextrin, carrageenan, and the like; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, and the like; Ingredients for chewable tablets include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), and the like; suspending/gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, and the like; Sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, and the like; Wet granulation agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, and the like.

“Alkyl” refers to and includes saturated, linear or branched monovalent hydrocarbon structures and combinations thereof. Particular alkyl groups are those having from 1 to 20 carbon atoms (“C ₁ -C ₂₀ alkyl”). More specific alkyl groups are those having 1 to 8 carbon atoms (“C ₁ -C ₈ alkyl”) or 1 to 6 carbon atoms (“C ₁ -C ₆ alkyl”). When referring to an alkyl moiety having a particular number of carbons, it is intended that all geometric isomers having that number of carbons are included and described; Thus, for example, “butyl” is meant to include n-butyl, sec-butyl, iso-butyl and tert-butyl; “Profile” includes n-propyl and iso-propyl. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like.

[0042] "Cycloalkyl" refers to and includes cyclic monovalent hydrocarbon structures. Cycloalkyls can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged or a combination thereof. Preferred cycloalkyls are saturated cyclic hydrocarbons having 3 to 13 ring carbon atoms. A more preferred cycloalkyl is a saturated cyclic hydrocarbon having 3 to 8 cyclic carbon atoms ("C ₃ -C ₈ cycloalkyl"). Examples of cycloalkyl groups include adamantyl, decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0043] "Alkenyl" refers to an unsaturated hydrocarbon group having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and preferably having from 2 to 10 carbon atoms, more preferably from 2 to 8 carbon atoms. Non-limiting examples of alkenyl include -CH ₂ -CH=CH-CH ₃ and -CH=CH-CH=CH ₂ .

[0044] "Cycloalkenyl" refers to an unsaturated hydrocarbon group within a cycloalkyl having at least one site of olefinic unsaturation (ie, having at least one moiety of the formula C=C). Cycloalkenyls can consist of one ring, such as cyclohexyl, or multiple rings, such as norbornenyl. A more preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having 3 to 8 cyclic carbon atoms ("C ₃ -C ₈ cycloalkenyl"). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.

[0045] "Alkynyl" refers to an unsaturated hydrocarbon group having at least one site of acetylenic unsaturation (i.e., at least one moiety of the formula C≡C), preferably from 2 to 10 carbon atoms, more preferably from 2 to 8 carbon atoms, and the like.

[0046] The term "alkoxy" refers to the -O alkyl group, where O is the point of attachment to the rest of the molecule, and alkyl is as defined above.

[0047] The term "thioalkoxy" refers to the group -S-alkyl, where S is the point of attachment to the rest of the molecule, and alkyl is as defined above.

[0048] "Haloalkyl" refers to an alkyl group having one or more halo substituents, such as 1, 2 or 3 halo substituents. Examples of haloalkyl groups are -CF ₃ , -(CH ₂ )F, -CHF ₂ , CH ₂ Br, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , and -CH ₂ CH ₂ F.

[0049] "Carbocycle", "carbocyclic", or "carbocyclyl" refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon group having a single ring or multiple condensed rings having from 3 to 13 cyclic carbon atoms. A carbocycle containing more than one ring may be fused, spiro, or bridged, or a combination thereof. One or more rings in a fused ring system may be aryl. Carbocycles having at least one ring in which at least one ring is aromatic may be linked to the parent structure at either a non-aromatic ring position or an aromatic ring position. In one variant, a carbocycle having one or more rings in which at least one ring is aromatic is linked to the parent structure at a non-aromatic ring position.

[0050] "Heterocycle", "heterocyclic" or "heterocyclyl" refers to a saturated or unsaturated non-aromatic group having a single ring or multiple condensed rings and having 1 to 10 cyclic carbon atoms and 1 to 4 cyclic carbon atoms. Heteroatoms such as nitrogen, sulfur or oxygen. Heterocycles comprising more than one ring may be fused, spiro or bridged, or any combination thereof. One or more rings in a fused ring system may be aryl or heteroaryl. Heterocycles having two or more rings in which at least one ring is aromatic may be linked to the parent structure either at a non-aromatic ring position or at an aromatic ring position. In one variant, a heterocycle having two or more rings in which at least one ring is aromatic is linked to the parent structure at a non-aromatic ring position.

“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic group having a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthryl) in which the condensed rings may or may not be aromatic. In one variation, the aryl group contains 6 to 14 cyclic carbon atoms. Aryl groups having two or more rings in which at least one ring is non-aromatic may be linked to the parent structure either at the aromatic ring position or at the non-aromatic ring position. In one variation, an aryl group having two or more rings in which at least one ring is non-aromatic is linked to the parent structure at an aromatic ring position.

[0052] "Heteroaryl" or "HetAr" refers to an unsaturated aromatic carbocyclic group having from 1 to 10 cyclic carbon atoms and at least one cyclic heteroatom including, but not limited to, heteroatoms such as nitrogen, oxygen and sulfur. Heteroaryl groups may have a single ring (eg, pyridyl, furyl) or multiple condensed rings (eg, indolizinyl, benzothienyl), and the condensed rings may or may not be aromatic. Heteroaryl groups having two or more rings in which at least one ring is non-aromatic may be linked to the parent structure either at the aromatic ring position or at the non-aromatic ring position. In one variation, a heteroaryl group having two or more rings in which at least one ring is non-aromatic is linked to the parent structure at an aromatic ring position.

[0053] The term "halogen" denotes chlorine, fluorine, bromine or iodine. The term "halo" denotes chloro, fluoro, bromo or iodo.

[0054] The term "substituted" means that the specified group or moiety is, by way of non-limiting examples, alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocyclyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy. The term "unsubstituted" means that the specified group has no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, substitution is meant to occur at any valence-permissive position on the system.

[0055] A "substantially pure" composition of compounds means that the composition contains no more than 15%, preferably no more than 10%, more preferably no more than 5%, even more preferably no more than 3%, and most preferably no more than 1% of impurities (which impurities may be compounds in other stereochemical forms). For example, a substantially pure composition of a compound (S) means that the (R) form of that compound is less than 15% or less than 10% or less than 5% or less than 3% or less than 1% of the composition.

[0056] Any formula described herein is intended to represent not only compounds having the structure depicted by the structural formula, but also compounds of the structure depicted in a particular variation or form. In particular, a compound of any formula provided herein, such as a compound of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), has an asymmetric center and therefore exists in several different enantiomeric forms. Such stereoisomeric mixtures may be separated into individual stereoisomers on the basis of physical, chemical or optical differences by methods known to those skilled in the art, for example by chromatography or fractional crystallization. All such isomers, including diastereomers and enantiomers, are considered part of the present invention. All optical isomers and stereoisomers of the compounds of the general formula and mixtures thereof in any ratio are considered to be within the scope of the corresponding formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. In addition, certain structures may exist as geometric isomers (ie, cis and trans isomers), tautomers, or atropisomers. Additionally, any formula given herein is intended to refer to any one of the hydrates, solvates, amorphous and polymorphic forms of these compounds, and mixtures thereof, even if such forms are not explicitly recited. In some embodiments, the solvent is water and the solvate is a hydrate.

[0057] Any formula given herein is also intended to represent unlabeled as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, 14 C, ¹⁵ N, ^{18 O} , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, and ¹²⁵ I, respectively. Substitution with heavier isotopes such as deuterium (ie ² H) may provide greater metabolic stability, eg increased in vivo half-life or certain therapeutic advantages arising from reduced dosage requirements. Isotopically labeled compounds and prodrugs thereof described herein can generally be prepared by substituting a non-isotopically labeled reagent for a readily available isotopically labeled reagent by following the schemes below or by carrying out the procedures disclosed in the Examples and Preparations.

[0058] When referring to any formula given herein, selection of a particular moiety from a list of possible species for a particular variable is not intended to define the same selection of species for a variable appearing elsewhere. That is, when a variable appears more than once, the selection of a species from one specified list is made independently of the selection of species for the same variable at other positions in the formula, unless otherwise stated.

[0059] In accordance with the foregoing interpretative considerations of assignment and nomenclature, explicit reference to a set herein is chemically significant and, unless indicated otherwise, an independent reference to and reference to each and every embodiment of such set is understood to mean possible implementations of a subset of the explicitly referenced set.

compound

[0060] The compounds and salts (eg, pharmaceutically acceptable salts) thereof are detailed herein, including the summary and appended claims. Also provided are geometric isomers (cis/trans), E/Z isomers, enantiomers, diastereomers and mixtures thereof in any ratio, including racemic mixtures, uses of the compounds herein, including salts and solvates of the foregoing compounds, and methods for preparing such compounds. Any compound described herein can also be referred to as a drug.

[0061] In one aspect, a compound of Formula (I),

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein:

G ¹ is N or CR ^a ;

G ² is N or CR ^b ;

n is 1 or 2;

m is 0, 1, 2 or 3;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ alkylamino, and optionally substituted aryloxy;

each R ¹ is independently selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;

or two R ¹ groups together with the carbon atoms to which they are connected form a 4- to 7-membered carbocyclic or heterocyclic ring optionally substituted by one or more R ^{a groups} ;

R²is hydrogen, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆Alkyl-O, optionally substituted C_One-C₆Alkyl-S, optionally substituted C_One-C₆Alkyl-SO₂, optionally substituted C_One-C₆Alkyl-NR^a, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆Alkynyl, optionally substituted aryl, optionally substituted aryl-O, optionally substituted aryl-S, optionally substituted aryl-SO₂, optionally substituted aryl-NR^a, optionally substituted cycloalkyl, optionally substituted cycloalkyl-O, optionally substituted cycloalkyl-S, optionally substituted cycloalkyl-SO₂, optionally substituted cycloalkylNR^a, optionally substituted heteroaryl, optionally substituted heteroaryl-O, optionally substituted heteroaryl-S, optionally substituted heteroaryl-SO₂, optionally substituted heteroaryl-NR^a, optionally substituted heterocyclyl, optionally substituted heterocyclyl-O, optionally substituted heterocyclyl-S, optionally substituted heterocyclyl-SO₂, and optionally substituted heterocyclyl-NR^aIt is selected from the group consisting of;

R ³ is selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;

R ⁴ is selected from the group consisting of:

(i) hydrogen;

(ii) C ₁ -C ₆ alkyl optionally substituted with one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, hydroxyl, heteroaryl, and optionally substituted heterocyclyl;

(iii) heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, acryloyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted C ₁ -C ₆ alkyl-NR ^a , and optionally substituted heterocyclyl;

(iv) aryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -C(O)O(C ₁ -C- ₆ alkyl), acryloylamino, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C 1 -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted C _{1 -C 6} alkyl-NR ^a , and optionally substituted heterocyclyl;

(v) heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted C ₁ -C ₆ alkyl-NR ^a , optionally substituted heteroaryl, and optionally substituted heterocyclyl;

(vi) carbonyl substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -NRa(C ₁ -C ₆ alkoxy), and optionally substituted heteroaryl; and

(vii) —SO ₂ (C ₁ -C ₆ alkyl);

R ⁵ is hydrogen, C ₁ -C ₆ alkyl, or heterocyclyl;

or R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

provided that R ² is 2,6-dichloro-3,5-dimethoxyphenyl:

R ⁴ is selected from the group consisting of:

(i) hydrogen;

(ii) C ₁ -C ₆ alkyl optionally substituted with one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, hydroxyl, heteroaryl, and optionally substituted heterocyclyl;

(iii) heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, acryloyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(iv) aryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -C(O)O(C ₁ -C- ₆ alkyl), optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(v) heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

(vi) carbonyl substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, —NRa(C ₁ -C ₆ alkoxy), and optionally substituted heteroaryl; and

(vii) —SO ₂ (C ₁ -C ₆ alkyl);

R ⁵ is hydrogen, C ₁ -C ₆ alkyl, or heterocyclyl;

or R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

[0062] In some embodiments, a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein:

G ¹ is N or CR ^a ;

G ² is N or CR ^b ;

n is 1 or 2;

m is 0, 1, 2 or 3;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ alkylamino, and optionally substituted aryloxy;

each R ¹ is independently selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;

or two R ¹ groups together with the carbon atoms to which they are connected form a 4- to 7-membered carbocyclic or heterocyclic ring optionally substituted by one or more R ^a groups;

R²is hydrogen, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆Alkyl-O, optionally substituted C_One-C₆Alkyl-S, optionally substituted C_One-C₆Alkyl-SO₂, optionally substituted C_One-C₆Alkyl-NR^a, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆Alkynyl, optionally substituted aryl, optionally substituted aryl-O, optionally substituted aryl-S, optionally substituted aryl-SO₂, optionally substituted aryl-NR^a, optionally substituted cycloalkyl, optionally substituted cycloalkyl-O, optionally substituted cycloalkyl-S, optionally substituted cycloalkyl-SO₂, optionally substituted cycloalkylNR^a, optionally substituted heteroaryl, optionally substituted heteroaryl-O, optionally substituted heteroaryl-S, optionally substituted heteroaryl-SO₂, optionally substituted heteroaryl-NR^a, optionally substituted heterocyclyl, optionally substituted heterocyclyl-O, optionally substituted heterocyclyl-S, optionally substituted heterocyclyl-SO₂, and optionally substituted heterocyclyl-NR^aIt is selected from the group consisting of;

R ³ is selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;

R ⁴ is selected from the group consisting of:

(i) hydrogen;

(ii) C ₁ -C ₆ alkyl optionally substituted with one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, hydroxyl, heteroaryl, and optionally substituted heterocyclyl;

(iii) heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, acryloyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(iv) aryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -C(O)O(C ₁ -C- ₆ alkyl), acryloylamino, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(v) heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

(vi) carbonyl substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, —NRa(C ₁ -C ₆ alkoxy), and optionally substituted heteroaryl; and

(vii) —SO ₂ (C ₁ -C ₆ alkyl);

R ⁵ is hydrogen, C ₁ -C ₆ alkyl, or heterocyclyl;

or R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

provided that R ² is 2,6-dichloro-3,5-dimethoxyphenyl:

R ⁴ is selected from the group consisting of:

(i) hydrogen;

(ii) C ₁ -C ₆ alkyl optionally substituted with one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, hydroxyl, heteroaryl, and optionally substituted heterocyclyl;

(iii) heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, acryloyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(iv) aryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -C(O)O(C ₁ -C- ₆ alkyl), optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(v) heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

(vi) carbonyl substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, —NRa(C ₁ -C ₆ alkoxy), and optionally substituted heteroaryl; and

(vii) —SO ₂ (C ₁ -C ₆ alkyl);

R ⁵ is hydrogen, C ₁ -C ₆ alkyl, or heterocyclyl;

or R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

[0063] In some embodiments, a compound of Formula (I),

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein:

G ¹ is N or CR ^a ;

G ² is N or CR ^b ;

n is 1 or 2;

m is 0, 1, 2 or 3;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ alkylamino, and optionally substituted aryloxy;

each R ¹ is each independently selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;

or two R ¹ groups together with the carbon atoms to which they are connected form a 4- to 7-membered carbocyclic or heterocyclic ring optionally substituted by one or more R ^a groups;

R ² is hydrogen;

optionally substituted C ₁ -C ₆ alkyl;

optionally substituted C ₁ -C ₆ alkyl-O;

optionally substituted C ₁ -C ₆ alkyl-S;

optionally substituted C ₁ -C ₆ alkyl-SO ₂ ,

optionally substituted C ₁ -C ₆ alkyl-NR ^a ,

optionally substituted C ₂ -C ₆ alkenyl;

optionally substituted C ₂ -C ₆ alkynyl;

halogen, hydroxyl, amino, cyano, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆alkoxy, optionally substituted C_One-C₆Thioalkoxy, NR^aCO-(optionally substituted C_One-C₆alkyl), NR^aCO-(optionally substituted aryl), NR^aCO-(optionally substituted heteroaryl), NR^aCO-(optionally substituted C₂-C₆alkynyl), NR^aCO-(optionally substituted cycloalkyl), NR^aCO-(optionally substituted heterocyclyl), CONR^a-(randomly substituted C_One-C₆alkyl), CONR^a-(optionally substituted aryl), CONR^a-(optionally substituted heteroaryl), CONR^a-(randomly substituted C₂-C₆alkynyl), CONR^a-(optionally substituted cycloalkyl), CONR^a-(optionally heterocyclyl), NR^aSO₂-(randomly substituted C_One-C₆alkyl), NR^aSO₂-(optionally substituted aryl), NR^aSO₂-(optionally substituted heteroaryl), NR^aSO₂-(randomly substituted C₂-C₆alkynyl), NR^aSO₂-(optionally substituted cycloalkyl), NR^aSO₂-(optionally heterocyclyl), SO₂NR^a-(randomly substituted C_One-C₆alkyl), SO₂NR^a-(optionally substituted aryl), SO₂NR^a-(optionally substituted heteroaryl), SO₂NR^a-(randomly substituted C₂-C₆alkynyl), SO₂NR^a-(optionally substituted cycloalkyl), SO₂NR^a-(optionally heterocyclyl), NR^aCONR^a-(randomly substituted C_One-C₆alkyl), NR^aCONR^a-(optionally substituted aryl), NR^aCONR^a-(optionally substituted heteroaryl), NR^aCONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCONR^a-(optionally substituted cycloalkyl), NR^aCONR^a-(optionally heterocyclyl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C_One-C₆alkyl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted aryl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted heteroaryl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCO-cycloalkylene-CONR^aaryl optionally substituted by one or more groups selected from the group consisting of -(optionally substituted cycloalkyl), and (optionally heterocyclyl);

halogen, hydroxyl, amino, cyano, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆alkoxy, optionally substituted C_One-C₆Thioalkoxy, NR^aCO-(optionally substituted C_One-C₆alkyl), NR^aCO-(optionally substituted aryl), NR^aCO-(optionally substituted heteroaryl), NR^aCO-(optionally substituted C₂-C₆alkynyl), NR^aCO-(optionally substituted cycloalkyl), NR^aCO-(optionally heterocyclyl), CONR^a-(randomly substituted C_One-C₆alkyl), CONR^a-(optionally substituted aryl), CONR^a-(optionally substituted heteroaryl), CONR^a-(randomly substituted C₂-C₆alkynyl), CONR^a-(optionally substituted cycloalkyl), CONR^a-(optionally heterocyclyl), NR^aSO₂-(randomly substituted C_One-C₆alkyl), NR^aSO₂-(optionally substituted aryl), NR^aSO₂-(optionally substituted heteroaryl), NR^aSO₂-(randomly substituted C₂-C₆alkynyl), NR^aSO₂-(optionally substituted cycloalkyl), NR^aSO₂-(optionally substituted heterocyclyl), SO₂NR^a-(randomly substituted C_One-C₆alkyl), SO₂NR^a-(optionally substituted aryl), SO₂NR^a-(optionally substituted heteroaryl), SO₂NR^a-(randomly substituted C₂-C₆alkynyl), SO₂NR^a-(optionally substituted cycloalkyl), SO₂NR^a-(optionally heterocyclyl), NR^aCONR^a-(randomly substituted C_One-C₆alkyl), NR^aCONR^a-(optionally substituted aryl), NR^aCONR^a-(optionally substituted heteroaryl), NR^aCONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCONR^a-(optionally substituted cycloalkyl), NR^aCONR^a-(optionally heterocyclyl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C_One-C₆alkyl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted aryl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted heteroaryl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCO-cycloalkylene-CONR^aAryl-O optionally substituted by one or more groups selected from the group consisting of -(optionally substituted cycloalkyl), and (optionally heterocyclyl);

optionally substituted aryl-S,

randomized

aryl-SO ₂ ;

optionally substituted aryl-NR ^a ,

halogen, hydroxyl, amino, cyano, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆alkoxy, optionally substituted C_One-C₆Thioalkoxy, NR^aCO-(optionally substituted C_One-C₆alkyl), NR^aCO-(optionally substituted aryl), NR^aCO-(optionally substituted heteroaryl), NR^aCO-(optionally substituted C₂-C₆alkynyl), NR^aCO-(optionally substituted cycloalkyl), NR^aCO-(optionally heterocyclyl), CONR^a-(randomly substituted C_One-C₆alkyl), CONR^a-(optionally substituted aryl), CONR^a-(optionally substituted heteroaryl), CONR^a-(randomly substituted C₂-C₆alkynyl), CONR^a-(optionally substituted cycloalkyl), CONR^a-(optionally He*(optionally substituted heterocyclyl), NR^aSO₂-(randomly substituted C_One-C₆alkyl), NR^aSO₂-(optionally substituted aryl), NR^aSO₂-(optionally substituted heteroaryl), NR^aSO₂-(randomly substituted C₂-C₆alkynyl), NR^aSO₂-(optionally substituted cycloalkyl), NR^aSO₂-(optionally heterocyclyl), SO₂NR^a-(randomly substituted C_One-C₆alkyl), SO₂NR^a-(optionally substituted aryl), SO₂NR^a-(optionally substituted heteroaryl), SO₂NR^a-(randomly substituted C₂-C₆alkynyl), SO₂NR^a-(optionally substituted cycloalkyl), SO₂NR^a-(optionally heterocyclyl), NR^aCONR^a-(randomly substituted C_One-C₆alkyl), NR^aCONR^a-(optionally substituted aryl), NR^aCONR^a-(optionally substituted heteroaryl), NR^aCONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCONR^a-(optionally substituted cycloalkyl), NR^aCONR^a-(optionally heterocyclyl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C_One-C₆alkyl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted aryl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted heteroaryl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCO-cycloalkylene-CONR^aheteroaryl optionally substituted by one or more groups selected from the group consisting of -(optionally substituted cycloalkyl), and (optionally heterocyclyl);

halogen, hydroxyl, amino, cyano, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆alkoxy, optionally substituted C_One-C₆Thioalkoxy, NR^aCO-(optionally substituted C_One-C₆alkyl), NR^aCO-(optionally substituted aryl), NR^aCO-(optionally substituted heteroaryl), NR^aCO-(optionally substituted C₂-C₆alkynyl), NR^aCO-(optionally substituted cycloalkyl), NR^aCO-(optionally heterocyclyl), CONR^a-(randomly substituted C_One-C₆alkyl), CONR^a-(optionally substituted aryl), CONR^a-(optionally substituted heteroaryl), CONR^a-(randomly substituted C₂-C₆alkynyl), CONR^a-(optionally substituted cycloalkyl), CONR^a-(optionally heterocyclyl), NR^aSO₂-(randomly substituted C_One-C₆alkyl), NR^aSO₂-(optionally substituted aryl), NR^aSO₂-(optionally substituted heteroaryl), NR^aSO₂-(randomly substituted C₂-C₆alkynyl), NR^aSO₂-(optionally substituted cycloalkyl), NR^aSO₂-(optionally heterocyclyl), SO₂NR^a-(randomly substituted C_One-C₆alkyl), SO₂NR^a-(optionally substituted aryl), SO₂NR^a-(optionally substituted heteroaryl), SO₂NR^a-(randomly substituted C₂-C₆alkynyl), SO₂NR^a-(optionally substituted cycloalkyl), SO₂NR^a-(optionally heterocyclyl), NR^aCONR^a-(randomly substituted C_One-C₆alkyl), NR^aCONR^a-(optionally substituted aryl), NR^aCONR^a-(optionally substituted heteroaryl), NR^aCONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCONR^a-(optionally substituted cycloalkyl), NR^aCONR^a-(optionally heterocyclyl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C_One-C₆alkyl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted aryl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted heteroaryl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCO-cycloalkylene-CONR^aHeteroaryl-O optionally substituted by one or more groups selected from the group consisting of -(optionally substituted cycloalkyl), and (optionally heterocyclyl);

optionally substituted heteroaryl-S;

optionally substituted heteroaryl-SO ₂ ,

optionally substituted heteroaryl-NR ^a ,

optionally substituted cycloalkyl,

optionally substituted cycloalkyl-O;

optionally substituted cycloalkyl-S,

optionally substituted cycloalkyl-SO ₂ ,

optionally substituted cycloalkylNR ^a ,

optionally substituted heterocyclyl;

optionally substituted heterocyclyl-O;

optionally substituted heterocyclyl-S;

optionally substituted heterocyclyl-SO ₂ , and optionally substituted heterocyclyl-NR ^a

It is selected from the group consisting of;

R ³ is selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;

R ⁴ is selected from the group consisting of:

(i) hydrogen;

(ii) C ₁ -C ₆ alkyl optionally substituted with one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, hydroxyl, heteroaryl, and optionally substituted heterocyclyl;

(iii) heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, acryloyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted C ₁ -C ₆ alkyl-NR ^a , and optionally substituted heterocyclyl;

(iv) aryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -C(O)O(C ₁ -C- ₆ alkyl), acryloylamino, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C 1 -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted C _{1 -C 6} alkyl-NR ^a , and optionally substituted heterocyclyl;

(v) heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted C ₁ -C ₆ alkyl-NR ^a , optionally substituted heteroaryl, and optionally substituted heterocyclyl;

(vi) carbonyl substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, —NRa(C ₁ -C ₆ alkoxy), and optionally substituted heteroaryl; and

(vii) —SO ₂ (C ₁ -C ₆ alkyl);

R ⁵ is hydrogen, C ₁ -C ₆ alkyl, or heterocyclyl;

or R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

provided that R ² is 2,6-dichloro-3,5-dimethoxyphenyl:

R ⁴ is selected from the group consisting of:

(i) hydrogen;

(ii) C ₁ -C ₆ alkyl optionally substituted with one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, hydroxyl, heteroaryl, and optionally substituted heterocyclyl;

(iii) heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, acryloyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(iv) aryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -C(O)O(C ₁ -C- ₆ alkyl), optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(v) heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

(vi) carbonyl substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, —NRa(C ₁ -C ₆ alkoxy), and optionally substituted heteroaryl; and

(vii) —SO ₂ (C ₁ -C ₆ alkyl);

R ⁵ is hydrogen, C ₁ -C ₆ alkyl, or heterocyclyl;

or R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

[0064] In some embodiments, a compound of Formula (I),

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein:

G ¹ is N or CR ^a ;

G ² is N or CR ^b ;

n is 1 or 2;

m is 0, 1, 2 or 3;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ alkylamino, and optionally substituted aryloxy;

each R ¹ is each independently selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;

or two R ¹ groups together with the carbon atoms to which they are connected form a 4- to 7-membered carbocyclic or heterocyclic ring optionally substituted by one or more R ^a groups;

R ² is hydrogen;

optionally substituted C ₁ -C ₆ alkyl;

optionally substituted C ₁ -C ₆ alkyl-O;

optionally substituted C ₁ -C ₆ alkyl-S;

optionally substituted C ₁ -C ₆ alkyl-SO ₂ ,

optionally substituted C ₁ -C ₆ alkyl-NR ^a ,

optionally substituted C ₂ -C ₆ alkenyl;

optionally substituted C ₂ -C ₆ alkynyl;

halogen, hydroxyl, amino, cyano, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆alkoxy, optionally substituted C_One-C₆Thioalkoxy, NR^aCO-(optionally substituted C_One-C₆alkyl), NR^aCO-(optionally substituted aryl), NR^aCO-(optionally substituted heteroaryl), NR^aCO-(optionally substituted C₂-C₆alkynyl), NR^aCO-(optionally substituted cycloalkyl), NR^aCO-(optionally substituted heterocyclyl), CONR^a-(randomly substituted C_One-C₆alkyl), CONR^a-(optionally substituted aryl), CONR^a-(optionally substituted heteroaryl), CONR^a-(randomly substituted C₂-C₆alkynyl), CONR^a-(optionally substituted cycloalkyl), CONR^a-(optionally heterocyclyl), NR^aSO₂-(randomly substituted C_One-C₆alkyl), NR^aSO₂-(optionally substituted aryl), NR^aSO₂-(optionally substituted heteroaryl), NR^aSO₂-(randomly substituted C₂-C₆alkynyl), NR^aSO₂-(optionally substituted cycloalkyl), NR^aSO₂-(optionally heterocyclyl), SO₂NR^a-(randomly substituted C_One-C₆alkyl), SO₂NR^a-(optionally substituted aryl), SO₂NR^a-(optionally substituted heteroaryl), SO₂NR^a-(randomly substituted C₂-C₆alkynyl), SO₂NR^a-(optionally substituted cycloalkyl), SO₂NR^a-(optionally heterocyclyl), NR^aCONR^a-(randomly substituted C_One-C₆alkyl), NR^aCONR^a-(optionally substituted aryl), NR^aCONR^a-(optionally substituted heteroaryl), NR^aCONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCONR^a-(optionally substituted cycloalkyl), NR^aCONR^a-(optionally heterocyclyl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C_One-C₆alkyl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted aryl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted heteroaryl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCO-cycloalkylene-CONR^aaryl optionally substituted by one or more groups selected from the group consisting of -(optionally substituted cycloalkyl), and (optionally heterocyclyl);

halogen, hydroxyl, amino, cyano, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆alkoxy, optionally substituted C_One-C₆Thioalkoxy, NR^aCO-(optionally substituted C_One-C₆alkyl), NR^aCO-(optionally substituted aryl), NR^aCO-(optionally substituted heteroaryl), NR^aCO-(optionally substituted C₂-C₆alkynyl), NR^aCO-(optionally substituted cycloalkyl), NR^aCO-(optionally heterocyclyl), CONR^a-(randomly substituted C_One-C₆alkyl), CONR^a-(optionally substituted aryl), CONR^a-(optionally substituted heteroaryl), CONR^a-(randomly substituted C₂-C₆alkynyl), CONR^a-(optionally substituted cycloalkyl), CONR^a-(optionally heterocyclyl), NR^aSO₂-(randomly substituted C_One-C₆alkyl), NR^aSO₂-(optionally substituted aryl), NR^aSO₂-(optionally substituted heteroaryl), NR^aSO₂-(randomly substituted C₂-C₆alkynyl), NR^aSO₂-(optionally substituted cycloalkyl), NR^aSO₂-(optionally substituted heterocyclyl), SO₂NR^a-(randomly substituted C_One-C₆alkyl), SO₂NR^a-(optionally substituted aryl), SO₂NR^a-(optionally substituted heteroaryl), SO₂NR^a-(randomly substituted C₂-C₆alkynyl), SO₂NR^a-(optionally substituted cycloalkyl), SO₂NR^a-(optionally heterocyclyl), NR^aCONR^a-(randomly substituted C_One-C₆alkyl), NR^aCONR^a-(optionally substituted aryl), NR^aCONR^a-(optionally substituted heteroaryl), NR^aCONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCONR^a-(optionally substituted cycloalkyl), NR^aCONR^a-(optionally heterocyclyl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C_One-C₆alkyl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted aryl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted heteroaryl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCO-cycloalkylene-CONR^aAryl-O optionally substituted by one or more groups selected from the group consisting of -(optionally substituted cycloalkyl), and (optionally heterocyclyl);

optionally substituted aryl-S,

randomized

aryl-SO ₂ ;

optionally substituted aryl-NR ^a ,

halogen, hydroxyl, amino, cyano, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆alkoxy, optionally substituted C_One-C₆Thioalkoxy, NR^aCO-(optionally substituted C_One-C₆alkyl), NR^aCO-(optionally substituted aryl), NR^aCO-(optionally substituted heteroaryl), NR^aCO-(optionally substituted C₂-C₆alkynyl), NR^aCO-(optionally substituted cycloalkyl), NR^aCO-(optionally heterocyclyl), CONR^a-(randomly substituted C_One-C₆alkyl), CONR^a-(optionally substituted aryl), CONR^a-(optionally substituted heteroaryl), CONR^a-(randomly substituted C₂-C₆alkynyl), CONR^a-(optionally substituted cycloalkyl), CONR^a-(optionally He*(optionally substituted heterocyclyl), NR^aSO₂-(randomly substituted C_One-C₆alkyl), NR^aSO₂-(optionally substituted aryl), NR^aSO₂-(optionally substituted heteroaryl), NR^aSO₂-(randomly substituted C₂-C₆alkynyl), NR^aSO₂-(optionally substituted cycloalkyl), NR^aSO₂-(optionally heterocyclyl), SO₂NR^a-(randomly substituted C_One-C₆alkyl), SO₂NR^a-(optionally substituted aryl), SO₂NR^a-(optionally substituted heteroaryl), SO₂NR^a-(randomly substituted C₂-C₆alkynyl), SO₂NR^a-(optionally substituted cycloalkyl), SO₂NR^a-(optionally heterocyclyl), NR^aCONR^a-(randomly substituted C_One-C₆alkyl), NR^aCONR^a-(optionally substituted aryl), NR^aCONR^a-(optionally substituted heteroaryl), NR^aCONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCONR^a-(optionally substituted cycloalkyl), NR^aCONR^a-(optionally heterocyclyl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C_One-C₆alkyl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted aryl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted heteroaryl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCO-cycloalkylene-CONR^aheteroaryl optionally substituted by one or more groups selected from the group consisting of -(optionally substituted cycloalkyl), and (optionally heterocyclyl);

halogen, hydroxyl, amino, cyano, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆alkoxy, optionally substituted C_One-C₆Thioalkoxy, NR^aCO-(optionally substituted C_One-C₆alkyl), NR^aCO-(optionally substituted aryl), NR^aCO-(optionally substituted heteroaryl), NR^aCO-(optionally substituted C₂-C₆alkynyl), NR^aCO-(optionally substituted cycloalkyl), NR^aCO-(optionally heterocyclyl), CONR^a-(randomly substituted C_One-C₆alkyl), CONR^a-(optionally substituted aryl), CONR^a-(optionally substituted heteroaryl), CONR^a-(randomly substituted C₂-C₆alkynyl), CONR^a-(optionally substituted cycloalkyl), CONR^a-(optionally heterocyclyl), NR^aSO₂-(randomly substituted C_One-C₆alkyl), NR^aSO₂-(optionally substituted aryl), NR^aSO₂-(optionally substituted heteroaryl), NR^aSO₂-(randomly substituted C₂-C₆alkynyl), NR^aSO₂-(optionally substituted cycloalkyl), NR^aSO₂-(optionally heterocyclyl), SO₂NR^a-(randomly substituted C_One-C₆alkyl), SO₂NR^a-(optionally substituted aryl), SO₂NR^a-(optionally substituted heteroaryl), SO₂NR^a-(randomly substituted C₂-C₆alkynyl), SO₂NR^a-(optionally substituted cycloalkyl), SO₂NR^a-(optionally heterocyclyl), NR^aCONR^a-(randomly substituted C_One-C₆alkyl), NR^aCONR^a-(optionally substituted aryl), NR^aCONR^a-(optionally substituted heteroaryl), NR^aCONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCONR^a-(optionally substituted cycloalkyl), NR^aCONR^a-(optionally heterocyclyl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C_One-C₆alkyl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted aryl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted heteroaryl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCO-cycloalkylene-CONR^aHeteroaryl-O optionally substituted by one or more groups selected from the group consisting of -(optionally substituted cycloalkyl), and (optionally heterocyclyl);

optionally substituted heteroaryl-S;

optionally substituted heteroaryl-SO ₂ ,

optionally substituted heteroaryl-NR ^a ,

optionally substituted cycloalkyl,

optionally substituted cycloalkyl-O;

optionally substituted cycloalkyl-S,

optionally substituted cycloalkyl-SO ₂ ,

optionally substituted cycloalkylNR ^a ,

optionally substituted heterocyclyl;

optionally substituted heterocyclyl-O;

optionally substituted heterocyclyl-S;

optionally substituted heterocyclyl-SO ₂ , and optionally substituted heterocyclyl-NR ^a

It is selected from the group consisting of;

R ³ is selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;

R ⁴ is selected from the group consisting of:

(i) hydrogen;

(ii) C ₁ -C ₆ alkyl optionally substituted with one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, hydroxyl, heteroaryl, and optionally substituted heterocyclyl;

(iii) heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, acryloyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(iv) aryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -C(O)O(C ₁ -C- ₆ alkyl), acryloylamino, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(v) heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

(vi) carbonyl substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -NRa(C ₁ -C ₆ alkoxy), and optionally substituted heteroaryl; and

(vii) —SO ₂ (C ₁ -C ₆ alkyl);

R ⁵ is hydrogen, C ₁ -C ₆ alkyl, or heterocyclyl;

or R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

provided that R ² is 2,6-dichloro-3,5-dimethoxyphenyl:

R ⁴ is selected from the group consisting of:

(i) hydrogen;

(ii) C ₁ -C ₆ alkyl optionally substituted with one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, hydroxyl, heteroaryl, and optionally substituted heterocyclyl;

(iii) heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, acryloyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(iv) aryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -C(O)O(C ₁ -C- ₆ alkyl), optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(v) heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

(vi) carbonyl substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, —NRa(C ₁ -C ₆ alkoxy), and optionally substituted heteroaryl; and

(vii) —SO ₂ (C ₁ -C ₆ alkyl);

R ⁵ is hydrogen, C ₁ -C ₆ alkyl, or heterocyclyl;

or R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

[0065] In some embodiments, a compound of formula (I):

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein:

G ¹ is N or CR ^a ;

G ² is N or CR ^b ;

n is 1 or 2;

m is 0, 1, 2 or 3;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ alkylamino, and optionally substituted aryloxy;

each R ¹ is independently selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;

or two R ¹ groups together with the carbon atoms to which they are connected form a 4- to 7-membered carbocyclic or heterocyclic ring optionally substituted by one or more R ^{a groups} ;

R²is hydrogen, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆Alkyl-O, optionally substituted C_One-C₆Alkyl-S, optionally substituted C_One-C₆Alkyl-SO₂, optionally substituted C_One-C₆Alkyl-NR^a, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆Alkynyl, optionally substituted aryl, optionally substituted aryl-O, optionally substituted aryl-S, optionally substituted aryl-SO₂, optionally substituted aryl-NR^a, optionally substituted heteroaryl, optionally substituted heteroaryl-O, optionally substituted heteroaryl-S, optionally substituted heteroaryl-SO₂, optionally substituted heteroaryl-NR^a, optionally substituted heterocyclyl, optionally substituted heterocyclyl-O, optionally substituted heterocyclyl-S, optionally substituted heterocyclyl-SO₂, and optionally substituted heterocyclyl-NR^aIt is selected from the group consisting of;

R ³ is selected from the group consisting of hydrogen, halogen, cyano, nitro, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;

R ⁴ is selected from the group consisting of:

(i) hydrogen;

(ii) C ₁ -C ₆ alkyl optionally substituted with optionally substituted heterocyclyl;

(iii) heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

(iv) aryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl; and

(v) heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;

R ⁵ is hydrogen, or C ₁ -C ₆ alkyl;

or R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl.

[0066] In some embodiments of Formula (I), G ¹ is N. In some embodiments, G ¹ is CR ^a , where R ^a is hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ alkylamino, and optionally substituted aryloxy. In some embodiments, G ¹ is CR ^a , wherein R ^a is selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy. In some embodiments, G ¹ is CH.

[0067] In some embodiments of Formula (I), G ² is N. In some embodiments, G ² is CR ^b , wherein R ^b is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ alkylamino, and optionally substituted aryloxy. In some embodiments, G ² is CR ^b , wherein R ^b is selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy. In some embodiments, G ² is CH. In some embodiments, G ² is CR ^b , wherein R ^b is an optionally substituted C ₁ -C ₆ alkyl. In some embodiments, G ² is CR ^b , wherein R ^b is C ₁ -C ₆ alkyl. In some embodiments, G ² is CR ^b , wherein R ^b is methyl.

[0068] In some embodiments of Formula (I), G ¹ is N and G ² is N. In some embodiments, G ¹ is CR ^a and G ² is N. In certain embodiments, G ¹ is CH and G ² is N. In some embodiments, G ¹ is N and G ² is CR ^b . In certain embodiments, G ¹ is N and G ² is CH. In some embodiments, G ¹ is N and G ² is CR ^b , wherein R ^b is C ₁ -C ₆ alkyl. In some embodiments, G ¹ is N and G ² is CR ^b and R ^b is methyl. In another embodiment, G ¹ is CR ^a and G ² is CR ^b . In some embodiments, G ¹ is CH and G ² is CH.

[0069] In some embodiments, a compound of Formula (I) is a compound of Formula (I-1a),

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, and n are as defined in Formula (I).

In some embodiments of Formula (I) or (I-1a), n is 1. In another embodiment, n is 2.

[0071] In some embodiments, a compound of Formula (I) is a compound of Formula (I-2a) or (I-2b),

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and m are as defined in formula (I).

In some embodiments of Formula (I), (I-1a), (I-2a), or (I-2b), m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In another embodiment, m is 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 and R ¹ is independently selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy. In some embodiments, m is 1 and R ¹ is an optionally substituted C ₁ -C ₆ alkyl. In some embodiments, m is 1 and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, m is 1 and R ¹ is methyl. In some embodiments, m is 2 or 3, and each R ¹ is independently selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy, or two R ¹ groups together with the carbon atoms to which they are connected form a 4- to 7-membered carbocyclic or heterocyclic ring optionally substituted by one or more R ^a groups. In some embodiments, m is 2 or 3, and each R ¹ is independently selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy. In some embodiments, m is 2 and each R ¹ is independently selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy; or two R ¹ groups together with the carbon atoms to which they are connected form a 4- to 7-membered carbocyclic or heterocyclic ring optionally substituted by one or more R ^a groups. In some embodiments, m is 2 and the two R ¹ groups together with the carbon atoms to which they are connected form a 4-7 membered carbocyclic or heterocyclic ring optionally substituted by one or more R ^a groups. In some embodiments, m is 2 and the two R ¹ groups together with the carbon atoms to which they are connected form a cyclopentane ring.

[0073] In some embodiments, a compound of Formula (I) is a compound of Formula (I-3a) or (I-3b),

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein R ² , R ³ , R ⁴ , and R ⁵ are as defined in Formula (I).

[0074] In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), R ³ is hydrogen. In some embodiments, R ³ is selected from the group consisting of hydrogen, halogen, cyano, nitro, optionally substituted C ₁ -C ₆ alkyl and optionally substituted C ₁ -C ₆ alkoxy. In some embodiments, R ³ is selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy. In some embodiments, R ³ is selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy. In some embodiments, R ³ is an optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ³ is C ₁ -C ₆ alkyl. In some embodiments, R ³ is methyl.

In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), R²is hydrogen, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆Alkyl-O, optionally substituted C_One-C₆Alkyl-S, optionally substituted C_One-C₆Alkyl-SO₂, optionally substituted C_One-C₆Alkyl-NR^a, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆Alkynyl, optionally substituted aryl, optionally substituted aryl-O, optionally substituted aryl-S, optionally substituted aryl-SO₂, optionally substituted aryl-NR^a, optionally substituted heteroaryl, optionally substituted heteroaryl-O, optionally substituted heteroaryl-S, optionally substituted heteroaryl-SO₂, optionally substituted heteroaryl-NR^a, optionally substituted heterocyclyl, optionally substituted heterocyclyl-O, optionally substituted heterocyclyl-S, optionally substituted heterocyclyl-SO₂, and optionally substituted heterocyclyl-NR^ais selected from the group consisting of

In some embodiments, R ² is hydrogen;

optionally substituted C ₁ -C ₆ alkyl;

optionally substituted C ₁ -C ₆ alkyl-O;

optionally substituted C ₁ -C ₆ alkyl-S;

optionally substituted C ₁ -C ₆ alkyl-SO ₂ ,

optionally substituted C ₁ -C ₆ alkyl-NR ^a ,

optionally substituted C ₂ -C ₆ alkenyl;

optionally substituted C ₂ -C ₆ alkynyl;

halogen, hydroxyl, amino, cyano, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆alkoxy, optionally substituted C_One-C₆Thioalkoxy, NR^aCO-(optionally substituted C_One-C₆alkyl), NR^aCO-(optionally substituted aryl), NR^aCO-(optionally substituted heteroaryl), NR^aCO-(optionally substituted C₂-C₆alkynyl), NR^aCO-(optionally substituted cycloalkyl), NR^aCO-(optionally substituted heterocyclyl), CONR^a-(randomly substituted C_One-C₆alkyl), CONR^a-(optionally substituted aryl), CONR^a-(optionally substituted heteroaryl), CONR^a-(randomly substituted C₂-C₆alkynyl), CONR^a-(optionally substituted cycloalkyl), CONR^a-(optionally heterocyclyl), NR^aSO₂-(randomly substituted C_One-C₆alkyl), NR^aSO₂-(optionally substituted aryl), NR^aSO₂-(optionally substituted heteroaryl), NR^aSO₂-(randomly substituted C₂-C₆alkynyl), NR^aSO₂-(optionally substituted cycloalkyl), NR^aSO₂-(optionally heterocyclyl), SO₂NR^a-(randomly substituted C_One-C₆alkyl), SO₂NR^a-(optionally substituted aryl), SO₂NR^a-(optionally substituted heteroaryl), SO₂NR^a-(randomly substituted C₂-C₆alkynyl), SO₂NR^a-(optionally substituted cycloalkyl), SO₂NR^a-(optionally heterocyclyl), NR^aCONR^a-(randomly substituted C_One-C₆alkyl), NR^aCONR^a-(optionally substituted aryl), NR^aCONR^a-(optionally substituted heteroaryl), NR^aCONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCONR^a-(optionally substituted cycloalkyl), NR^aCONR^a-(optionally heterocyclyl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C_One-C₆alkyl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted aryl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted heteroaryl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCO-cycloalkylene-CONR^aaryl optionally substituted by one or more groups selected from the group consisting of -(optionally substituted cycloalkyl), and (optionally heterocyclyl);

halogen, hydroxyl, amino, cyano, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆alkoxy, optionally substituted C_One-C₆Thioalkoxy, NR^aCO-(optionally substituted C_One-C₆alkyl), NR^aCO-(optionally substituted aryl), NR^aCO-(optionally substituted heteroaryl), NR^aCO-(optionally substituted C₂-C₆alkynyl), NR^aCO-(optionally substituted cycloalkyl), NR^aCO-(optionally heterocyclyl), CONR^a-(randomly substituted C_One-C₆alkyl), CONR^a-(optionally substituted aryl), CONR^a-(optionally substituted heteroaryl), CONR^a-(randomly substituted C₂-C₆alkynyl), CONR^a-(optionally substituted cycloalkyl), CONR^a-(optionally heterocyclyl), NR^aSO₂-(randomly substituted C_One-C₆alkyl), NR^aSO₂-(optionally substituted aryl), NR^aSO₂-(optionally substituted heteroaryl), NR^aSO₂-(randomly substituted C₂-C₆alkynyl), NR^aSO₂-(optionally substituted cycloalkyl), NR^aSO₂-(optionally substituted heterocyclyl), SO₂NR^a-(randomly substituted C_One-C₆alkyl), SO₂NR^a-(optionally substituted aryl), SO₂NR^a-(optionally substituted heteroaryl), SO₂NR^a-(randomly substituted C₂-C₆alkynyl), SO₂NR^a-(optionally substituted cycloalkyl), SO₂NR^a-(optionally heterocyclyl), NR^aCONR^a-(randomly substituted C_One-C₆alkyl), NR^aCONR^a-(optionally substituted aryl), NR^aCONR^a-(optionally substituted heteroaryl), NR^aCONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCONR^a-(optionally substituted cycloalkyl), NR^aCONR^a-(optionally heterocyclyl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C_One-C₆alkyl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted aryl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted heteroaryl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCO-cycloalkylene-CONR^aAryl-O optionally substituted by one or more groups selected from the group consisting of -(optionally substituted cycloalkyl), and (optionally heterocyclyl);

optionally substituted aryl-S,

randomized

aryl-SO ₂ ;

optionally substituted aryl-NR ^a ,

halogen, hydroxyl, amino, cyano, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆alkoxy, optionally substituted C_One-C₆Thioalkoxy, NR^aCO-(optionally substituted C_One-C₆alkyl), NR^aCO-(optionally substituted aryl), NR^aCO-(optionally substituted heteroaryl), NR^aCO-(optionally substituted C₂-C₆alkynyl), NR^aCO-(optionally substituted cycloalkyl), NR^aCO-(optionally heterocyclyl), CONR^a-(randomly substituted C_One-C₆alkyl), CONR^a-(optionally substituted aryl), CONR^a-(optionally substituted heteroaryl), CONR^a-(randomly substituted C₂-C₆alkynyl), CONR^a-(optionally substituted cycloalkyl), CONR^a-(optionally He*(optionally substituted heterocyclyl), NR^aSO₂-(randomly substituted C_One-C₆alkyl), NR^aSO₂-(optionally substituted aryl), NR^aSO₂-(optionally substituted heteroaryl), NR^aSO₂-(randomly substituted C₂-C₆alkynyl), NR^aSO₂-(optionally substituted cycloalkyl), NR^aSO₂-(optionally heterocyclyl), SO₂NR^a-(randomly substituted C_One-C₆alkyl), SO₂NR^a-(optionally substituted aryl), SO₂NR^a-(optionally substituted heteroaryl), SO₂NR^a-(randomly substituted C₂-C₆alkynyl), SO₂NR^a-(optionally substituted cycloalkyl), SO₂NR^a-(optionally heterocyclyl), NR^aCONR^a-(randomly substituted C_One-C₆alkyl), NR^aCONR^a-(optionally substituted aryl), NR^aCONR^a-(optionally substituted heteroaryl), NR^aCONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCONR^a-(optionally substituted cycloalkyl), NR^aCONR^a-(optionally heterocyclyl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C_One-C₆alkyl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted aryl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted heteroaryl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCO-cycloalkylene-CONR^aheteroaryl optionally substituted by one or more groups selected from the group consisting of -(optionally substituted cycloalkyl), and (optionally heterocyclyl);

halogen, hydroxyl, amino, cyano, optionally substituted C_One-C₆Alkyl, optionally substituted C_One-C₆alkoxy, optionally substituted C_One-C₆Thioalkoxy, NR^aCO-(optionally substituted C_One-C₆alkyl), NR^aCO-(optionally substituted aryl), NR^aCO-(optionally substituted heteroaryl), NR^aCO-(optionally substituted C₂-C₆alkynyl), NR^aCO-(optionally substituted cycloalkyl), NR^aCO-(optionally heterocyclyl), CONR^a-(randomly substituted C_One-C₆alkyl), CONR^a-(optionally substituted aryl), CONR^a-(optionally substituted heteroaryl), CONR^a-(randomly substituted C₂-C₆alkynyl), CONR^a-(optionally substituted cycloalkyl), CONR^a-(optionally heterocyclyl), NR^aSO₂-(randomly substituted C_One-C₆alkyl), NR^aSO₂-(optionally substituted aryl), NR^aSO₂-(optionally substituted heteroaryl), NR^aSO₂-(randomly substituted C₂-C₆alkynyl), NR^aSO₂-(optionally substituted cycloalkyl), NR^aSO₂-(optionally heterocyclyl), SO₂NR^a-(randomly substituted C_One-C₆alkyl), SO₂NR^a-(optionally substituted aryl), SO₂NR^a-(optionally substituted heteroaryl), SO₂NR^a-(randomly substituted C₂-C₆alkynyl), SO₂NR^a-(optionally substituted cycloalkyl), SO₂NR^a-(optionally heterocyclyl), NR^aCONR^a-(randomly substituted C_One-C₆alkyl), NR^aCONR^a-(optionally substituted aryl), NR^aCONR^a-(optionally substituted heteroaryl), NR^aCONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCONR^a-(optionally substituted cycloalkyl), NR^aCONR^a-(optionally heterocyclyl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C_One-C₆alkyl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted aryl), NR^aCO-cycloalkylene-CONR^a-(optionally substituted heteroaryl), NR^aCO-cycloalkylene-CONR^a-(randomly substituted C₂-C₆alkynyl), NR^aCO-cycloalkylene-CONR^aheteroaryl-O optionally substituted by one or more groups selected from the group consisting of -(optionally substituted cycloalkyl), and (optionally heterocyclyl);

optionally substituted heteroaryl-S;

optionally substituted heteroaryl-SO ₂ ,

optionally substituted heteroaryl-NR ^a ,

optionally substituted cycloalkyl,

optionally substituted cycloalkyl-O;

optionally substituted cycloalkyl-S,

optionally substituted cycloalkyl-SO ₂ ,

optionally substituted cycloalkylNR ^a ,

optionally substituted heterocyclyl;

optionally substituted heterocyclyl-O;

optionally substituted heterocyclyl-S;

optionally substituted heterocyclyl-SO ₂ , and optionally substituted heterocyclyl-NR ^a

is selected from the group consisting of In some embodiments, R ² is selected from the group consisting of hydrogen, optionally substituted C ₂ -C ₆ alkynyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments, R ² is hydrogen. In some embodiments, R ² is optionally substituted C ₂ -C ₆ alkynyl. In some embodiments, R ² is C ₂ -C ₆ alkynyl substituted with aryl, heteroaryl, or heterocyclyl. In some embodiments, R ² is C ₂ -C ₆ alkynyl substituted with C 6 -C ₁₄ aryl, 5-12 membered heteroaryl, or _3-12 membered heterocyclyl. In some embodiments, R ² is C ₂ -C ₆ alkynyl substituted with a 5- or 6-membered heteroaryl.

[0076] In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), R ² is optionally substituted aryl. In some embodiments, R ² is an optionally substituted C ₆ -C ₁₄ aryl. In certain embodiments, R ² is phenyl or naphthyl. In some embodiments, R ² is aryl substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, hydroxyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl. In some embodiments, R ² is C ₆ -C ₁₄ aryl substituted by one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, hydroxyl, optionally substituted 5-12 membered heteroaryl, and optionally substituted 3-12 membered heterocyclyl. In certain embodiments, R ² is phenyl substituted by one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, hydroxyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocyclyl. In some embodiments, R ² is C ₆ -C ₁₄ aryl substituted with 1 or 2 halo groups. In certain embodiments, R ² is phenyl substituted with 1 or 2 halo groups. In some embodiments, R ² is phenyl substituted with chloro. In some embodiments, R ² is phenyl substituted with 2 chloro groups. In some embodiments, R ² is C ₆ -C ₁₄ aryl substituted by a halo substituent and an additional substituent selected from the group consisting of C 1 -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxyl, optionally substituted 5-12 membered heteroaryl, _and optionally substituted 3-12 membered heterocyclyl. In some embodiments, R ² is phenyl substituted with halo and optionally substituted 5- to 6-membered heteroaryl. In another embodiment, R ² is phenyl substituted with halo and optionally substituted 5- to 6-membered heterocyclyl. In certain embodiments, R ² is a 5- to 6-membered heterocyclyl optionally substituted with one or more groups selected from oxo and C ₁ -C ₆ alkyl and phenyl substituted with chloro. In another embodiment, R ² is a 5- to 6-membered heteroaryl optionally substituted with one or more groups selected from oxo and C ₁ -C ₆ alkyl and phenyl substituted with chloro. In some embodiments, R ² is C ₆ -C ₁₄ aryl substituted with C ₁ -C ₆ alkyl. In certain embodiments, R ² is phenyl substituted with C ₁ -C ₆ alkyl, such as phenyl substituted with methyl. In some embodiments, R ² is C ₆ -C ₁₄ aryl substituted with C ₁ -C ₆ alkoxy. In some embodiments, R ² is phenyl substituted with C ₁ -C ₆ alkoxy, such as phenyl substituted with methoxy. In some embodiments, R ² is C ₆ -C ₁₄ aryl substituted with hydroxyl. In some embodiments, R ² is phenyl substituted with hydroxyl. In other embodiments, R ² is C ₆ -C ₁₄ aryl substituted with one or more groups selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and hydroxyl.

[0077] In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), R ² is optionally substituted heteroaryl. In some embodiments, R ² is an optionally substituted 5-12 membered heteroaryl. In some embodiments, R ² is an optionally substituted 5- or 6-membered heteroaryl. In some embodiments, R ² is an unsubstituted 5- or 6-membered heteroaryl. In some embodiments, R ² is a 5- or 6-membered heteroaryl optionally substituted by one or more groups selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and hydroxyl. In some embodiments, R ² is a 5- or 6-membered heteroaryl optionally substituted with C ₁ -C ₆ alkyl. In some embodiments, R ² is optionally substituted heterocyclyl. In some embodiments, R ² is an optionally substituted 3-12 membered heterocyclyl. In some embodiments, R ² is an optionally substituted 5- or 6-membered heterocyclyl. In some embodiments, R ² is a 5- or 6-membered heterocyclyl optionally substituted by one or more groups selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxyl, and oxo.

[0078] In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b)

is selected from the group consisting of In some embodiments R ² is H;

[0079] In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), R ⁴ is: (i) hydrogen; (ii) C ₁ -C ₆ alkyl optionally substituted by one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, hydroxyl, heteroaryl, and optionally substituted heterocyclyl; (iii) heterocyclyl optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, acryloyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl; (iv) aryl optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, -C(O)O(C ₁ -C- ₆ alkyl), acryloylamino, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl; (v) heteroaryl optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted heteroaryl, and optionally substituted heterocyclyl; (vi) carbonyl substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -NRa(C ₁ -C ₆ alkoxy), and optionally substituted heteroaryl; and (vii) -SO ₂ (C ₁ -C ₆ alkyl). In some embodiments, R ⁴ is: (i) hydrogen; (ii) C ₁ -C ₆ alkyl optionally substituted with optionally substituted heterocyclyl; (iii) heterocyclyl optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl; (iv) aryl optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl; and (v) heteroaryl optionally substituted by one or more groups selected from the group consisting _of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C 6 alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl.

In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), R ⁴ is hydrogen.

[0081] In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), R ⁴ is C ₁ -C ₆ alkyl optionally substituted with optionally substituted heterocyclyl.

[0082] In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), R ⁴ is one or more selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl. Heterocyclyl optionally substituted by a group. In some embodiments, R ⁴ is a 3-12 membered heterocyclyl. In some embodiments, R ⁴ is a 3-12 membered heterocycloalkyl. In some embodiments, R ⁴ is oxetanyl or tetrahydropyranyl. In some embodiments, R ⁴ is 3-oxetanyl or 4-tetrahydropyranyl. In some embodiments, R ⁴ is 3-oxetanyl. In some embodiments, R ⁴ is 4-tetrahydropyranyl.

[0083] In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), R ⁴ is halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted 3- _{to 12-membered heterocyclyl and C 6 -C 14 aryl} optionally substituted by one or more groups selected from the group consisting of In some embodiments, R ⁴ is phenyl optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted 5- or 6-membered heterocyclyl. In some embodiments, R ⁴ is phenyl optionally substituted with halogen. In some embodiments, R ⁴ is phenyl optionally substituted with fluoro. In some embodiments, R ⁴ is phenyl optionally substituted with hydroxyl. In some embodiments, R ⁴ is phenyl optionally substituted with optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ⁴ is phenyl substituted with C ₁ -C ₆ alkyl further substituted with hydroxyl. In some embodiments, R ⁴ is C 6 -C ₁₄ aryl substituted by one additional substituent selected from the group consisting of halo and hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy _, and optionally substituted 3-12 membered heterocyclyl. In some embodiments, R ⁴ is phenyl substituted by one additional substituent selected from the group consisting of halo and hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted 5- or 6-membered heterocyclyl. In some embodiments, R ⁴ is phenyl substituted by fluoro and optionally substituted 5- or 6-membered heterocyclyl. In certain embodiments, R ⁴ is phenyl substituted by fluoro and optionally substituted piperazinyl. In some _embodiments , R ⁴ is C ₆ -C ₁₄ aryl substituted with optionally substituted C 1 -C ₆ alkoxy. In some embodiments, R ⁴ is C ₆ -C ₁₄ aryl substituted with C ₁ -C ₆ alkoxy optionally substituted with —N(C ₁ -C ₆ alkyl) ₂ . In some embodiments, R ⁴ is phenyl substituted with C ₁ -C ₆ alkoxy or C ₁ -C ₆ thioalkoxy.

[0084] In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), R ⁴ is one or more selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl. heteroaryl optionally substituted by a group. In some embodiments, R ⁴ is a 5-12 membered heteroaryl optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted 3-12 membered heterocyclyl. In some embodiments, R ⁴ is a 5- or 6-membered heteroaryl optionally substituted by one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and optionally substituted 5- or 6-membered heterocyclyl. In some embodiments, R ⁴ is a 5- or 6-membered heteroaryl substituted with halo. In certain embodiments, R ⁴ is pyridyl substituted with halo. In some embodiments, R ⁴ is pyridyl. In some embodiments, R ⁴ is a 5- or 6-membered heteroaryl substituted with C ₁ -C ₆ alkyl. In some embodiments, R ⁴ is a 5- or 6-membered heteroaryl substituted with C ₁ -C ₆ alkoxy. In some embodiments, R ⁴ is a 5- or 6-membered heteroaryl substituted with C ₁ -hydroxyl.

[0085] In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), R ⁴ is hydrogen, methyl, ethyl,

[0086] In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), R ⁵ is hydrogen. In some embodiments, R ⁵ is C ₁ -C ₆ alkyl. In some embodiments, R ⁵ is methyl. In some embodiments, R ⁵ is heterocyclyl. In some embodiments, R ⁵ is 3-oxetanyl.

[0087] In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl. In some embodiments, R ⁴ and R ⁵ together with the nitrogen to which they are attached form a substituted or unsubstituted 5- or 6-membered heterocyclyl. In certain embodiments, R ⁴ and R ⁵ together with the nitrogen to which they are attached form piperazinyl optionally substituted with a 5- or 6-membered heteroaryl. In some embodiments of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), silver am. In some embodiments, R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heteroaryl. In some embodiments, R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted pyrazole. In some embodiments, R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heteroaryl. In some embodiments, R ⁴ and R ⁵ together with the nitrogen to which they are attached form 5-amino-1H-pyrazol-1-yl.

[0088] Where applicable, any embodiment described herein for Formula (I) applies equally to Formulas (I-1a), (I-2a), (I-2b), (I-3a), and (I-3b). Also, a description of any variable of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a) or (I-3b) may be combined with one or more recitations of other variables, where applicable, as if each and every combination of variables were specifically and individually recited. For example, all statements about R ² are equally combinable with all statements about G ¹ , G ² , R ¹ , R ³ , R ⁴ , R ⁵ , m, and n, as if each and every combination were specifically and individually listed. Likewise, all statements about R ² are equally combinable with all statements about G ¹ , G ² , R ¹ , R ² , R ³ , R ⁵ , m, and n, as if each and every combination were specifically and individually listed.

[0089] In one variation, compounds of formulas provided herein contain one or more of the following structural features: (i) G ¹ is N; (ii) G ² is CH; (iii) m is 0; (iv) R ³ is hydrogen; and (v) R ⁵ is hydrogen.

In some embodiments, provided herein are compounds of Formulas (I), (I-1a), (I-2a), (I-2b), (I-3a), and (I-3b), or pharmaceutically acceptable salts thereof.

[0091] In some embodiments, provided herein are compounds described in Table 1 and salts thereof, and uses thereof.

Table 1

[0092] In some embodiments, provided herein are compounds described in Table 2 and salts thereof, and uses thereof.

Table 2

and pharmaceutically acceptable salts thereof.

[0093] Any formula or compound provided herein, such as Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), or a compound of Table 1 or Table 2, is intended to represent a compound having a particular variation or form, as well as the structure depicted by the structural formula. In particular, compounds of any of the formulas provided herein may have asymmetric centers and therefore may exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula and mixtures thereof in any proportion are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. Where a compound of Table 1 or Table 2 is depicted in a particular stereochemical configuration, any alternative stereochemical configuration of the compound as well as mixtures of stereoisomers of the compound in any ratio are provided herein. For example, if a compound of Table 1 or Table 2 has a stereocenter in the "S" stereochemical configuration, enantiomers of the compound whose stereocenter is in the "R" stereochemical configuration are also provided herein. Similarly, when a compound of Table 1 or Table 2 has a stereocenter in the "R" configuration, enantiomers of the compound in the "S" stereochemical configuration are also provided herein. Also provided are mixtures of compounds having the "S" and "R" stereochemical configurations. Additionally, when a compound of Table 1 or Table 2 has two or more stereocenters, any enantiomer or diastereomer of the compound is also provided. In addition, certain structures may exist as geometric isomers (ie, cis and trans isomers), tautomers, or atropisomers. Additionally, any compound in Table 1 or Table 2 is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. In addition, certain structures may exist as geometric isomers (ie, cis and trans isomers), tautomers, or atropisomers. Additionally, any formula given herein, such as Formula (I), (I-1a), (I-2a), (I-2b), (I-3a) or (I-3b), is intended to refer to a hydrate. , solvates and amorphous forms of these compounds and mixtures thereof, even if these forms are not explicitly listed. In some embodiments, the solvent is water and the solvate is a hydrate.

[0094] It is understood that the compounds described herein may exist as salts even when salts are not described, and that the compositions and methods provided herein include all salts and solvates of the compounds described herein, as well as non-salt and non-solvate forms, as is well understood by those skilled in the art. In some embodiments, a salt of a compound provided herein is a pharmaceutically acceptable salt.

[0095] In one variation, a compound herein is a synthetic compound prepared for administration to a subject. In another variation, a composition containing the compound in substantially pure form is provided. In another variation, a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier is provided. In another variation, a method of administering a compound is provided. Purified forms, pharmaceutical compositions and methods of administering the compound are suitable for any compound or form thereof described herein.

[0096] Any variation or embodiment of G ¹ , G ² , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, and n provided herein is combined with each and every other variation or embodiment of G ¹ , G ² , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, and n, as if each combination had been individually and specifically described. can be combined.

composition

[0097] Also provided are compositions, such as pharmaceutical compositions, comprising a compound disclosed and/or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, carriers, excipients, and the like. Suitable medicinal and pharmaceutical formulations include those described herein. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described above in admixture with at least one pharmaceutically acceptable carrier or excipient. In some embodiments, compositions are provided, such as pharmaceutical compositions, containing one or more compounds described herein, or pharmaceutically acceptable salts thereof.

[0098] In some embodiments, a compound of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b), or Table 1 or Table A pharmaceutically acceptable composition comprising the compound of 2 or a pharmaceutically acceptable salt thereof is provided. In some aspects, the compositions may contain synthetic intermediates that can be used in the preparation of the compounds described herein. The compositions described herein may contain any other suitable active or inactive agent.

[0099] Any of the compositions described herein may be sterile or contain sterile ingredients. Sterilization can be accomplished by methods known in the art. Any of the compositions described herein may contain one or more substantially pure compounds.

[0100] Also provided is a packaged pharmaceutical composition comprising a pharmaceutical composition as described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.

Pharmaceutical Formulations

[0101] The present disclosure also provides compositions, eg, pharmaceutical compositions, containing one or more compounds described herein formulated with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention may also be administered in combination therapy, ie in combination with other agents. For example, combination therapy can include a compound as described herein in combination with at least one other active agent.

[0102] Pharmaceutically acceptable carriers may include any physiologically compatible carriers, excipients, stabilizers, solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Preferably, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (eg by injection or infusion). Depending on the route of administration, the active compound, i.e., the compound described herein, may be coated with a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.

[0103] Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at standard dosages and concentrations to be administered, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol, etc.); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt forming counterions such as sodium; metal complexes (eg Zn-protein complexes); and/or nonionic surfactants such as TWEEN™ or polyethylene glycol (PEG).

[0104] The pharmaceutical composition of the present invention may include one or more pharmaceutically acceptable salts. Pharmaceutically acceptable salts retain the desired biological activity of the parent compound and do not impart undesirable toxic effects. Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, as well as non-toxic organic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorus, and the like. Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, calcium, and the like, as well as non-toxic organic amines such as N,N'dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like.

[0105] The pharmaceutical composition of the present invention may also include a pharmaceutically acceptable antioxidant. Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) fat-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like. Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by using coating materials such as lecithin, or by maintaining the required particle size in the case of dispersions, or by using surfactants.

[0106] Any suitable formulation of a compound described herein may be prepared. See generally, Remington's Pharmaceutical Sciences, (2000) Hoover, J. E. editor, 20 th edition, Lippincott Williams and Wilkins Publishing Company, Easton, Pa., pages 780-857. Formulations are selected to suit the appropriate route of administration. It may be appropriate to administer the compound as a salt when the compound is sufficiently basic or acidic to form stable, non-toxic acid or base salts. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Suitable inorganic salts may also be formed including hydrochloride, sulfate, nitrate, bicarbonate and carbonate salts. Pharmaceutically acceptable salts are obtained using standard procedures well known in the art, for example with sufficiently basic compounds such as amines with appropriate acids providing physiologically acceptable anions. Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts of carboxylic acids are also made.

[0107] When a contemplated compound is administered as a pharmacological composition, it is contemplated that the compound may be formulated in admixture with pharmaceutically acceptable excipients and/or carriers. For example, a contemplated compound may be administered orally as a neutral compound or pharmaceutically acceptable salt or intravenously with physiological saline. Conventional buffers such as phosphate, bicarbonate or citrate may be used for this purpose. Of course, one skilled in the art can modify the formulation within the teachings of the specification to provide a variety of formulations for a particular route of administration. In particular, a contemplated compound may be modified so that it is more soluble in water or other vehicle, which may be readily accomplished with minor modifications (salt formulations, esterification, etc.), eg, within the skill of the art. It is also within the ordinary skill in the art to modify the route of administration and dosing regimen of a particular compound to manage the pharmacokinetics of the compound for maximum beneficial effect on the patient.

[0108] Compounds having Formulas (I) to III described herein are generally soluble in organic solvents such as chloroform, dichloromethane, ethyl acetate, ethanol, methanol, isopropanol, acetonitrile, glycerol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and the like. In one embodiment, the present invention provides a formulation prepared by mixing a compound having formula (I)-III with a pharmaceutically acceptable carrier. In one aspect, the formulation comprises the steps of a) dissolving the described compound in a water soluble organic solvent, nonionic solvent, water soluble lipid, cyclodextrin, vitamin such as tocopherol, fatty acid, fatty acid ester, phospholipid or a combination thereof to provide a solution; and b) adding saline or a buffer containing a 1-10% carbohydrate solution. In one example, the carbohydrate includes dextrose. Pharmaceutical compositions obtained using the method of the present invention are stable and useful for animal and clinical applications.

Illustrative examples of water-soluble organic solvents for use in the method include, but are not limited to, polyethylene glycol (PEG), alcohols, acetonitrile, N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or combinations thereof. Examples of alcohols include but are not limited to methanol, ethanol, isopropanol, glycerol or propylene glycol.

[0110] A non-limiting example of a water-soluble nonionic surfactant for use in the present method is CREMOPHOR^® EL, polyethylene glycol modified CREMOPHOR® (polyoxyethyleneglycerol triricinolate 35), hydrogenated CREMOPHOR® RH40, hydrogenated CREMOPHOR® RH60, succinate, polysorbate 20, polysorbate 80, SOLUTOL® HS (polyethylene glycol 660 12-hydroxystearate), sorbitan monooleate, poloxamer, LABR AFIL® (ethoxylated persic oil), LABRASOL® (capryl-caproyl macrogol-8-glycerides), GELUCIRE® (glycerol) esters), SOFTIGEN® (PEG 6 caprylic acid glycerides), glycerin, glycol-polysorbates, or combinations thereof.

[0111] Non-limiting examples of water-soluble lipids for use in the method include vegetable oils, triglycerides, vegetable oils, or combinations thereof. Non-limiting examples of lipid oils include castor oil, polyoxyl castor oil, corn oil, olive oil, cottonseed oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, triglycerides of coconut oil, palm seed oil, and hydrogenated forms thereof, or combinations thereof.

[0112] Illustrative examples of fatty acids and fatty acid esters for use in the present method include, but are not limited to, mono- or di-fatty acid esters of oleic acid, monoglycerides, diglycerides, PEG, or combinations thereof.

[0113] Illustrative examples of cyclodextrins for use in the method include, but are not limited to, alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, or sulfobutyl ether-beta-cyclodextrin.

[0114] Illustrative examples of phospholipids for use in the present method include, but are not limited to, soybean phosphatidylcholine, or distearoyl phosphatidylglycerol, and hydrogenated forms thereof or combinations thereof.

[0115] One skilled in the art can modify the formulation within the teachings of the specification to provide a variety of formulations for specific routes of administration. In particular, a compound may be modified to be more soluble in water or other vehicle. It is also within the ordinary skill in the art to modify the route of administration and dosing regimen of a particular compound to manage the pharmacokinetics of the compound for maximum beneficial effect on the patient.

drug combination

[0116] The method of an embodiment comprises administering an effective amount of at least one exemplary compound of the present disclosure; Optionally the compound may be administered with one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is known to be useful in treating a proliferative disorder such as cancer or a tumor in a subject. In some embodiments, additional therapeutic agents are known to be useful for treating neurodegenerative disorders.

[0117] The additional active ingredient may be administered in a separate pharmaceutical composition from at least one exemplary compound of the present disclosure or may be included together with at least one exemplary compound of the present disclosure in a single pharmaceutical composition. Additional active ingredients can be administered simultaneously with, before, or after administration of at least one exemplary compound of the present invention.

Dosage and dosage form

[0118] For the prophylaxis or treatment of disease, the appropriate dosage of a compound described herein will depend on the type of disease being treated, the severity and course of the disease, whether the compound is administered for prophylactic or therapeutic purposes, the mode of delivery, previous treatments, and the subject's clinical history. A compound described herein is suitably administered to a subject at one time or over a series of treatments. Depending on the type and severity of the disease, a typical daily dosage may range from about 0.0001 mg/kg to 100 mg/kg or more, depending on the factors mentioned above. In the case of repeated administration over several days or more, depending on the condition, treatment is continued until the desired suppression of disease symptoms occurs.

[0119] For example, the dosage may be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg. The treatment schedule may include dosing once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once a month, once every 3 months or once every 3 to 6 months. In another embodiment, a sustained release formulation is administered, which will result in less frequent dosing compared to non-sustained release formulations.

[0120] The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will generally be that amount of the composition that will produce a therapeutic effect without being toxic to the subject. Generally, this amount will range from about 0.01% to about 99%, preferably from about 0.1% to about 70%, and most preferably from about 1% to about 30% of the active ingredient in combination with a pharmaceutically acceptable carrier.

administration

[0121] A composition described herein may be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary with the desired results. Routes of administration of the compounds and compositions described herein include oral, sublingual, buccal, intranasal, topical, rectal, intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, such as injection or infusion. The expression "parenteral administration" herein refers to modes of administration other than enteral and topical administration, generally by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

treatment method

[0122] The compounds and pharmaceutical compositions herein may be used for any suitable purpose. For example, the compounds may be used in therapy and/or testing.

[0123] The compounds and pharmaceutical compositions herein may be used to treat and/or prevent a proliferative disorder such as cancer or tumor in a subject. In some embodiments, provided is a method of treating or preventing a proliferative disorder, such as cancer or tumor, in an individual in need thereof, comprising administering to the individual a compound of Formula (I), (I-1a), (1-1a), (1-2a), (1-2b), (1-3a), (1-3b), or Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, methods are provided for treating or preventing a proliferative disorder, such as cancer or a tumor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein.

[0124] In some embodiments, a compound of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b), or a compound of Table 1 or Table 2 or a pharmaceutically acceptable salt thereof is one or more keys selected from the group consisting of MAPK, PDGFR, Src, PAKs, c-Kit, EphA2, EphB4, FGFR, Axl and c-Met inhibitors of cytokines, and therefore they are all suitable for therapeutic use as anti-proliferative or anti-metastatic agents (eg, anti-cancer agents) in mammals, especially humans. In particular, the compounds of the present invention are useful for the prevention and treatment of various human hyperproliferative disorders, such as malignant and benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, hepatocarcinoma, sarcoma, glioblastoma, head and neck cancer, melanoma, and other hyperplastic conditions such as benign hyperplasia of the skin (eg psoriasis) and benign hyperplasia of the prostate (eg BPH). It is also expected that the compounds of the present invention may have activity against brain metastases derived from these diseases.

[0125] In some embodiments, a compound of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b), or a compound of Table 1 or Table 2 or a pharmaceutically acceptable salt thereof may also be useful in the treatment of additional disorders involving abnormally expressed ligand/receptor interactions or activation or signaling events involving various kinases. Such disorders may include disorders of a neuronal, glial, astrocyte, hypothalamic and other glandular, macrophage, epithelial, stromal and blastoclastic nature involving abnormal function, expression, activation or signaling of tyrosine kinases.

[0126] Also provided is the use of a compound of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b) or Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a proliferative disorder such as cancer or tumor in a subject.

[0127] In some embodiments, the proliferative disorder or cancer is selected from the group consisting of a malignant or benign tumor of the liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, or liver. hepatocarcinoma, sarcoma, glioblastoma, malignant or benign tumors of the head and neck, melanoma, and other hyperplastic conditions such as benign hyperplasia of the skin (eg psoriasis) and benign hyperplasia of the prostate (eg BPH). In some embodiments, a compound of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b), or a compound of Table 1 or Table 2, may have activity against brain metastases resulting from these disorders.

[0128] Also provided are methods of inhibiting the activity of one or more kinases, such as MAPK, PDGFR, Src, PAKs, c-Kit, EphA2, EphB4, FGFR, Axl, and c-Met, comprising administering to a subject in need thereof a therapeutically effective amount of at least one chemical entity described herein. In some embodiments, a method of inhibiting one or more kinases such as MAPK, PDGFR, Src, PAKs, c-Kit, EphA2, EphB4, FGFR, Axl, and c-Met comprising contacting a cell with a compound of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b) or Table 1 or Table 2 or a pharmaceutically acceptable salt thereof Provided. Further, for preparing a medicament for inhibiting the activity of one or more kinases in a subject, such as MAPK, PDGFR, Src, PAKs, c-kit, EphA2, EphB4, FGFR, Axl and c-Met in a subject, a compound of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b) or a compound of Table 1 or Table 2, or a pharmaceutical The use of acceptable salts thereof is also provided.

[0129] Also provided is a method of treating and/or preventing a proliferative disorder such as cancer or a tumor in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one chemical entity described herein, such as a compound of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b), or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. Also provided are methods for treating and/or preventing proliferative disorders, such as cancer or tumors, in a subject. Further Formulas (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b), a compound of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b), or a compound of Table 1 or Table 2, or a pharmaceutical composition for preparing a medicament for the treatment and/or prevention of a proliferative disorder, cancer or tumor in a subject. The use of acceptable salts thereof is also provided.

[0130] In one embodiment, the disease or condition to be treated or prevented is an abnormal cell proliferation, such as cancer. The term “cancer” refers to precancerous conditions, non-malignant, low-grade, high-grade and malignant cancers. Cancer of any tissue type is contemplated for treatment or prophylaxis with the compounds disclosed herein. Exemplary types of cancer include carcinomas, lymphomas, blastomas, sarcomas, leukemias and lymphoid malignancies. More specifically, in certain embodiments the cancer is squamous cell cancer (e.g., epithelial squamous cell carcinoma), lung cancer, including small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, lung cancer, peritoneal cancer, hepatocellular cancer, gastric or intestinal cancer, including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, or uterus. Cancer includes cancer of the stomach or gastric adenocarcinoma, including salivary gland, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocarcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.

[0131] Provided herein is a method of treating cancer in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or composition described herein. Also provided herein is the use of a compound or composition described herein in the manufacture of a medicament for the treatment of cancer in a subject in need thereof. Also provided herein is the use of a compound or composition described herein for the treatment of cancer in an individual in need thereof. Also provided herein is a compound or composition described herein for use in the treatment of cancer in an individual in need thereof.

[0132] In another embodiment, the disease or condition to be treated or prevented is a neurodegenerative disease. Exemplary types of neurodegenerative diseases include, but are not limited to, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease, which occur as a result of neurodegenerative processes.

[0133] In some embodiments, a method for treating or preventing neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease is provided, comprising administering to an individual in need thereof a compound of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b), or Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. include that In some embodiments, methods are provided for treating or preventing neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease, comprising administering to a subject a therapeutically effective amount of at least one chemical entity as described herein.

[0134] Provided herein are methods of treating a neurodegenerative disease in an individual in need thereof by administering to the individual a therapeutically effective amount of a compound or composition described herein. Also provided herein is the use of a compound or composition described herein in the manufacture of a medicament for the treatment of a neurodegenerative disease in an individual in need thereof. Also provided herein is the use of a compound or composition described herein for the treatment of a neurodegenerative disease in a subject in need thereof. Also provided herein is a compound or composition described herein for use in the treatment of a neurodegenerative disease in a subject in need thereof.

[0135] In one aspect, provided herein is a kit containing a compound or composition described herein and instructions for use. In some embodiments, a kit may include instructions for use in treating cancer in an individual in need thereof. In another embodiment, a kit may include instructions for use in the treatment of a neurodegenerative disease in a subject in need thereof. A kit may further contain any material or equipment that can be used for administration of a compound or composition, such as a vial, syringe, or IV bag. Kits may also include sterile packaging.

General synthesis method

[0136] The compounds of formula (I) are described below with reference to illustrative synthetic schemes for general preparation below and specific examples below. One skilled in the art will recognize that appropriate selection of the starting materials may be used to obtain the various compounds herein so that the desired substituents can ultimately yield the desired product with or without appropriate protection through the reaction scheme. Alternatively, in place of the ultimately desired substituent, it may be necessary or desirable to use a suitable group that can be carried through the reaction scheme and can be appropriately replaced with the desired substituent. In addition, those skilled in the art will recognize that protecting groups can be used to protect certain functional groups (amino, carboxy or side groups) from reaction conditions and that such groups are removed under standard conditions where appropriate. Unless otherwise specified, the variables are as defined above with respect to Formula (I).

[0137] When it is desired to obtain a particular enantiomer of a compound, this may be achieved from the corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reacting mixtures of enantiomers, for example mixtures of racemates and appropriate chiral compounds. The diastereomers may be separated and the desired enantiomer recovered by any convenient means, for example crystallization. In another separation process, racemates can be separated using chiral high-performance liquid chromatography. Alternatively, if desired, specific enantiomers can be obtained using appropriate chiral intermediates in one of the processes described.

[0138] Chromatography, recrystallization and other conventional separation procedures may also be used for intermediates or final products for which it is desirable to obtain a particular isomer of a compound or otherwise purify the reaction product.

[0139] General methods for preparing the compounds described herein are described in the exemplified methods below. Variables in the reaction schemes provided herein are defined for formula (I), (I-1a), (I-2a), (I-2b), (I-3a), (I-3b) or any variation thereof. Other compounds described herein can be prepared by similar methods.

[0140] General synthetic methods referenced for preparing compounds of the present invention, such as B1, are described in Claudi F. et al, J. Org. chemistry. 1974, 39, p. 3508]. Certain starting materials may be prepared according to methods familiar to those skilled in the art and certain synthetic transformations may be performed according to methods familiar to those skilled in the art. A standard procedure for preparing 2-alkyl-1-iminoquinazolines is provided by Bartra Sanmarti, M. et al., WO2011/076813.

In some embodiments, a compound of formula (I) is synthesized via the method shown in Scheme A.

wherein G ¹ , G ² , R ² , R ³ , R ⁴ , R ⁵ , and n are as defined in Formula (I), or any variation thereof described herein. Specific examples are provided in the Examples section below.

In some embodiments, a compound of Formula (I) is synthesized via the method shown in Scheme B.

wherein G ¹ , G ² , R ² , R ³ , R ⁴ , R ⁵ , and n are as defined in Formula (I), or any variation thereof described herein. Specific examples are provided in the Examples section below.

[0143] Starting materials whose synthesis is not specifically described are commercially available or can be prepared using methods well known to those skilled in the art.

In some embodiments, the compound of Formula (I) is synthesized via the method shown in Scheme C.

wherein G ¹ , G ² , R ² , R ³ , R ⁴ , R ⁵ , and n are as defined in Formula (I), or any variation thereof described herein. Specific examples are provided in the Examples section below.

[0145] In some embodiments, a compound of formula (I) is synthesized via the method shown in Scheme D.

wherein G ¹ , G ² , R ² , R ³ , R ⁴ , R ⁵ , and n are as defined in Formula (I), or any variation thereof described herein. Specific examples are provided in the Examples section below.

Example

[0146] The following examples are provided to illustrate the compositions, uses and methods provided herein without limiting them to those described. One skilled in the art will appreciate that the following synthetic reactions and schemes may be modified by the selection of suitable starting materials and reagents to access other compounds of Formula (I), (I-1a), (I-2a), (I-2b), (I-3a), or (I-3b), or salts thereof. The compounds are prepared using the general methods described above.

[0147] The following chemical abbreviations are used throughout the examples: ACN (acetonitrile), DCM (dichloromethane), DIEA (N,N-diisopropylethylamine), DMF (dimethylformamide), DMAP (4-dimethylaminopyridine), DMSO (dimethyl sulfoxide), EtN (triethylamine), EtOAc (ethyl acetate), 1H NMR (proton nuclear magnetic resonance), HP High performance liquid chromatography (LC), isopropyl alcohol (i-PrOH), potassium acetate (KOAc), liquid chromatography-mass spectrometry (LCMS), lithium bis(trimethylsilyl)amide (LiHMDS), meta-chloroperoxybenzoic acid (m-CPBA), methyl iodide (MeI), methanol (MeOH), methanesulfonyl chloride (NMP), N-methyl-2-pyrrolidone (NMP) , Pd₂(dba)₃(tris(dibenzylideneacetone)diphalidium(0)), Pd(dppf)Cl₂ (1,1′-bis(diphenylphosphino)ferrocene palladium dichloride), PE (ferrolium ether), SEMCl (2-(trimethylsilyl)ethoxymethylchloride), THF (tetrahydrofuran), TLC (thin layer chromatography), and TFA (trifluoroacetic acid).

Example 1:6 -(2,4- dichlorophenyl )-N-(3- Fluoro Preparation of -4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (Compound 1)

[0148] Step 1: Synthesis of 6-(2,4-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0149] To a solution of 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (2.0 g, 11.8 mmol) in THF (100 mL) was added LiHMDS (30 mL). It was added dropwise at -78 °C. The reaction mixture was stirred at -70 °C for 2 hours. Then methyl 2-(2,4-dichlorophenyl)acetate (5.4 g, 24.8 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. NH ₄ Cl aq (30 mL) was added to the reaction mixture, and the solid was filtered and concentrated in vacuo to give 6-(2,4-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2.0 g, 50% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 338.0.

[0150] Step 2: Synthesis of 7-chloro-6-(2,4-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine

[0151] To a solution of 6-(2,4-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2.0 g, 5.91 mmol) in CH ₃ CN (40 mL) was added POCl ₃ (18.0 g, 0.12 mol). The mixture was stirred at 100 °C for 16 h under N ₂ . The mixture was concentrated in vacuo to give 7-chloro-6-(2,4-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine (2.2 g, crude) as a white solid, which was used directly in the next step. LCMS (M+H ⁺ ) m/z: 355.9.

Step 3: Synthesis of 2-((6-(2,4-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol

[0153] A solution of 7-chloro-6-(2,4-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine (2.2 g, crude, from step 2) and 2-aminoethane-1-ol (20 mL) was stirred at 90 °C for 2 h under N ₂ . The mixture was added to water (100 mL) and filtered to give 2-((6-(2,4-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (2.1 g, crude) as a white solid which was used directly in the next step. LCMS (M+H ⁺ ) m/z: 381.0.

[0154] Step 4: Synthesis of 6-(2,4-dichlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0155] To a solution of 2-((6-(2,4-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (1.0 g, 2.62 mmol) and Et ₃ N (794 mg, 7.86 mmol) in DCM (40 mL) was added methanesulfonyl chloride (450 mg, 3.93 mmol) at 0°C. was added under N ₂ . The reaction mixture was added under N ₂ at room temperature for 16 hours. The mixture was extracted with DCM (30 mL x 3), washed with brine (50 mL), then dried over Na ₂ SO ₄ , concentrated and purified by column chromatography on silica gel (DCM/MeOH = 80:1) to give 6-(2,4-dichlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (615 mg, 65% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 363.0.

[0156] Step 5: Synthesis of 6-(2,4-dichlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0157] To a solution of 6-(2,4-dichlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (200 mg, 0.55 mmol) in CH ₃ CN (5 mL) and H ₂ O (5 mL) was added Oxone (507 mg, 0.82 mmol). The reaction mixture was stirred at 30° C. under N ₂ for 48 hours. The mixture was adjusted to pH = 7-8 with 1N NaOH aq, extracted with DCM (10 mL x 3), washed with brine (50 mL), dried over Na ₂ SO ₄ , concentrated in vacuo and purified by preparative-TLC (PE/EtOAc = 1:1) to give 6-(2,4-dichlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1, 6]pyrido[2,3-d]pyrimidine (45 mg, 21% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 395.0.

[0158] Step 6: Synthesis of tert-butyl 4-(4-((6-(2,4-dichlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate

[0159] To a solution of 6-(2,4-dichlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (45 mg, 0.11 mmol) in DMSO (3 mL) was added tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (33 mg, 0. 11 mmol) was added. The reaction mixture was stirred at 120° C. for 1 hour under N ₂ . The mixture was added to water, extracted with EtOAc (10 mL x 3), washed with brine (50 mL), dried over Na ₂ SO ₄ then concentrated in vacuo and purified by column chromatography on silica gel (PE/EtOAc = 1:1) to yield tert-butyl 4-(4-((6-(2,4-dichlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d Obtained ]pyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (40 mg, 57% yield) as a black oil. LCMS (M+H ⁺ ) m/z: 610.2.

[0160] Step 7: Synthesis of 6-(2,4-dichlorophenyl)-N-(3-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0161] To a solution of tert-butyl 4-(4-((6-(2,4-dichlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (40 mg, 0.065 mmol) in DCM (1 mL), add TFA (1 mL) did The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and purified by prep-HPLC (0.1% TFA, MeCN in H ₂ O) to give 6-(2,4-dichlorophenyl)-N-(3-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (8.0 mg, 24% yield, TFA salt) was obtained as a white solid. ^1H NMR (400 MHz, CD ₃ OD): δ 8.98 (s, 1H), 8.19 (s, 1H), 7.88-7.84 (m, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.57 -7.48 (m, 3H), 7.14 (t, J = 9.2 Hz, 1 H), 4.92-4.86 (m, 2H), 4.22-4.17 (m, 2H), 3.42-3.38 (m, 4H), 3.34-3.32 (m, 4H). LCMS (M+H ⁺ ) m/z: 510.3.

Example 2:6 -(2,4- dichlorophenyl )-N-(3- Fluoro -4-(4- Methylpiperazine -1-yl) phenyl) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (compound 2) of manufacturing

[0162] Step 1: Synthesis of 6-(2,4-dichlorophenyl)-N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0163] To a solution of 6-(2,4-dichlorophenyl)-N-(3-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (20 mg, 0.039 mmol) in MeOH (2 mL) was added paraformaldehyde (2 mg, 0.078 mmol). added. After stirring for 15 min, NaBH ₃ CN (7 mg, 0.078 mmol) was added. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was purified by preparative-HPLC (0.1% TFA/CH ₃ CN/H ₂ O) to obtain 6-(2,4-dichlorophenyl)-N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (4.8 mg, 22% yield, T FA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.06 (s, 1H), 8.26 (s, 1H), 7.87 (s, 1H), 7.80 (d, J = 12.8 Hz, 1H), 7.65-7.54 (m, 3H), 7.16 (t, J = 9.2 Hz, 1H) , 4.80–4.66 (m, 2H), 4.16–4.06 (m, 2H), 3.66–3.46 (m, 4H), 3.30–3.18 (m, 2H), 3.08–2.98 (m, 2H), 2.88 (s, 3H). LCMS (M+H ⁺ ) m/z: 524.2.

Example 3:6 -(2,4- dichlorophenyl )-N-(4-(4- Ethylpiperazine -1-day)-3- fluorophenyls ) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (compound 3) of manufacturing

[0164] Step 1: Synthesis of 6-(2,4-dichlorophenyl)-N-(4-(4-ethylpiperazin-1-yl)-3-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0165] To a solution of 6-(2,4-dichlorophenyl)-N-(3-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (22 mg, 0.043 mmol) in MeOH (2 mL) was added acetaldehyde (0.1 mL, 0.086 mmol) was added. After stirring for 15 min, NaBH ₃ CN (8 mg, 0.086 mmol) was added. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was purified by preparative-HPLC (0.1% TFA/CH ₃ CN/H ₂ O) to give 6-(2,4-dichlorophenyl)-N-(4-(4-ethylpiperazin-1-yl)-3-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (4.3 mg, 18% yield, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.02 (s, 1H), 8.23-8.20 (m, 1H), 7.88 (s, 1H), 7.81 (d, J = 14.4 Hz, 1H), 7.66-7.53 (m, 3H), 7.15 (t, J = 9.2 Hz) , 1H), 4.76–4.60 (m, 2H), 4.09 (t, J = 9.6 Hz, 2H), 3.64–3.52 (m, 2H), 3.26–3.96 (m, 8H), 1.26 (t, J = 7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 538.2.

Example 4:6 -(2,4- dichlorophenyl )-N-ethyl-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 4)

[0166] Step 1: Synthesis of 6-(2,4-dichlorophenyl)-N-ethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0167] To a solution of 6-(2,4-dichlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (80 mg, 0.20 mmol) in DMF (4 mL) was added ethanamine (2 mL, 1M in THF). The mixture was stirred at 120° C. in a sealed test tube for 1 hour. The residue was purified by preparative-HPLC (0.1% TFA/CH ₃ CN/H ₂ O) to give 6-(2,4-dichlorophenyl)-N-ethyl-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (53 mg, 56% yield, TFA salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.92 (d, J = 31.6 Hz, 1H), 8.18 (s, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 8.4, 2.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 4.66-4.60 (m, 2H), 4.06-4.03 (m, 2H), 3.51-3.42 (m, 2H), 1.24-1.14 (m, 3H). LCMS (M+H ⁺ ) m/z: 360.1.

Example 5:6 -(2,4- dichlorophenyl )-N-( tetrahydro -2H-pyran-4-yl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 5)

[0168] Step 1: Synthesis of 6-(2,4-dichlorophenyl)-N-(tetrahydro-2H-pyran-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0169] To a solution of 6-(2,4-dichlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (80 mg, 0.20 mmol) in DMF (4 mL) was added tetrahydro-2H-pyran-4-amine (24 mg, 0.24 mmol). The mixture was stirred at 120° C. under N ₂ for 1 hour. The residue was purified by preparative-HPLC (0.1% TFA/CH ₃ CN/H ₂ O) to give 6-(2,4-dichlorophenyl)-N-(tetrahydro-2H-pyran-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40.48 mg, 39% yield, TFA salt). Obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.93 (d, J = 23.2 Hz, 1H), 8.17 (s, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 8.4, 2.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 4.69-4.57 (m, 2H), 4.18-4.00 (m, 3H), 3.94-3.89 (m, 2H), 3.47-3.38 (m, 2H), 1.95-1.81 (m, 2H), 1.65-1.55 (m, 2H). LCMS (M+H ⁺ ) m/z: 416.1.

Example 6:6 -(2,4- dichlorophenyl )-N-(2- fluorophenyls )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 6)

[0170] Step 1: Synthesis of 6-(2,4-dichlorophenyl)-N-(2-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0171] To a solution of 6-(2,4-dichlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (90 mg, 0.22 mmol) in DMF (3 mL) was added 2-fluoroaniline (30 mg, 0.27 mmol). The mixture was stirred at 120° C. under N ₂ for 1 hour. The residue was purified by preparative-HPLC (0.1% TFA/CH ₃ CN/H ₂ O) to afford 6-(2,4-dichlorophenyl)-N-(2-fluorophenyl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (17 mg, 18% yield, TFA salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.03 (s, 1H), 8.26 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.79-7.73 (m, 1H), 7.63 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.36–7.25 (m, 3H), 4.70–4.60 (m, 2H), 4.10–4.00 (m, 2H). LCMS (M+H ⁺ ) m/z: 426.1.

Example 7:6 -(2,4- dichlorophenyl )-N-(2- Fluoro Preparation of -4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (Compound 7)

[0172] Step 1: Synthesis of tert-butyl 4-(4-((6-(2,4-dichlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate

[0173] To a solution of 6-(2,4-dichlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (1.2 g, 3.16 mmol) in DMSO (10 mL) was added tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (744 mg, 2.53 mmol) was added. The reaction mixture was stirred at 120° C. for 2 h under N ₂ . The mixture was added to water, extracted with EtOAc (10 mL x 3), washed with brine (50 mL), dried over Na ₂ SO ₄ , concentrated and purified by preparative-TLC (EtOAc) to yield tert-butyl 4-(4-((6-(2,4-dichlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine- Obtained 2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (410 mg, 26% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 610.3.

[0174] Step 2: Synthesis of 6-(2,4-dichlorophenyl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0175] To a solution of tert-butyl 4-(4-((6-(2,4-dichlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (410 mg, 0.67 mmol) in MeOH (2 mL), HCl/dioxane (5 mL, 3M) was added. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated to give crude (380 mg) and 80 mg of crude was purified by preparative-HPLC (0.1% TFA/CH ₃ CN/H ₂ O) to obtain 6-(2,4-dichlorophenyl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] Pyrimidin-2-amine (37.1 mg, 46% yield, TFA salt) was obtained as a tan replacement. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.02-8.93 (m, 1H), 8.24 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.37-7.30 (m, 1H), 6.98 (d, J = 14.0 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.74-4.40 (m, 2H), 4.12-3.94 (m, 2H), 3.43-3.38 (m, 4H), 3.27-3.22 (m, 4H). LCMS (M+H ⁺ ) m/z: 510.2.

Example 8:6 -(2,4- dichlorophenyl )-N-(2- Fluoro -4-(4- Methylpiperazine -1-yl) phenyl) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (compound 8) of manufacturing

[0176] Step 1: Synthesis of 6-(2,4-dichlorophenyl)-N-(2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0177] To a solution of 6-(2,4-dichlorophenyl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (65 mg, 0.12 mmol) in MeOH (3 mL) was added paraformaldehyde (7 mg, 0.25 mmol). . After stirring for 15 min, NaBH ₃ CN (16 mg, 0.25 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour under N ₂ . The residue was purified by preparative-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to give 6-(2,4-dichlorophenyl)-N-(2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (31.3 mg, 47% yield, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.03-8.96 (m, 1H), 8.24 (s, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.65-7.62 (m, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.35 (br, 1H), 6.99 (d, J = 14.0 Hz, 1H), 6.88 (d, J = 11.6 Hz, 1H), 4.66-4.48 (m, 2H), 4.05-4.03 (m, 2H), 3.92-3.88 (m, 2H), 3.55-3.52 (m, 2H), 3.20-3.14 (m, 2H), 3.04-2.98 (m, 2H), 2.88 (s, 3H). LCMS (M+H ⁺ ) m/z: 524.2.

Example 9:6 -(2,4- dichlorophenyl )-N-(4-(4- Ethylpiperazine -1- days)-2- fluorophenyls ) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (compound 9) of manufacturing

[0178] Step 1: Synthesis of 6-(2,4-dichlorophenyl)-N-(4-(4-ethylpiperazin-1-yl)-2-fluorophenyl)-5,6,8,9-tetrahydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0179] To a solution of 6-(2,4-dichlorophenyl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (80 mg, 0.15 mmol) in MeOH (3 mL) is added acetaldehyde (0.1 mL, 5M in THF). did After stirring for 15 min, NaBH ₃ CN (20 mg, 0.31 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours under N ₂ . The mixture was purified by preparative-HPLC (0.1% HCl, CH ₃ CN in H ₂ O) to obtain 6-(2,4-dichlorophenyl)-N-(4-(4-ethylpiperazin-1-yl)-2-fluorophenyl)-5,6,8,9-tetrahydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (25 mg, 30% aqueous rate) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 540.2.

[0180] Step 2: Synthesis of 6-(2,4-dichlorophenyl)-N-(4-(4-ethylpiperazin-1-yl)-2-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

DDQ ( 28 mg, 0.12 mmol) was added. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated and purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to give 6-(2,4-dichlorophenyl)-N-(4-(4-ethylpiperazin-1-yl)-2-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (5.5 mg, 25% yield) , TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.03-8.92 (m, 1H), 8.24 (s, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.63 (dd, J = 8.0, 1.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.40 (br, 1H), 7.00 (d, J = 13.2 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 4.66-4.50 (m, 2H), 4.08-4.02 (m, 2H), 3.94-3.90 (m, 2H), 3.24-2.99 (m, 8H), 1.27 (t, J = 7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 538.3.

Example 10: N-(2- Fluoro -4-(piperazin-1-yl)phenyl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 10)

[0182] Step 1: Synthesis of tert-butyl 4-(4-((8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate

[0183] Pd/C (5 mg) was added. The mixture was stirred at room temperature under H ₂ for 16 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was used in the next step without purification.

[0184] Step 2: Synthesis of N-(2-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0185] To a solution of tert-butyl 4-(4-((8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (38 mg, 0.08 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to afford N-(2-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (15 mg, 50% yield, TFA salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.58 (br, 1H), 10.04 (br, 1H), 9.10-8.90 (m, 3H), 8.21 (d, J = 9.2 Hz, 1H), 7.52-7.37 (m, 1H), 6.96 (dd, J = 13.6, 2.0 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 4.45-4.30 (m, 2H), 4.08-4.04 (m, 2H), 3.50-3.39 (m, 4H), 3.26-3.25 (m, 4H). LCMS (M+H ⁺ ) m/z: 366.1.

Example 11:6 -(2- chlorophenyl )-N-(3- Fluoro Preparation of -4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (Compound 11)

[0186] Step 1: Synthesis of 6-(2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0187] To a solution of 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (10 g, 59.2 mmol) in NMP (130 mL) was added methyl 2-(2-chlorophenyl)acetate (22 g , 118.3 mmol) and K ₂ CO ₃ (25 g, 181.2 mmol) were added. The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was cooled to room temperature, water was added dropwise and stirred for 1 hour. The solid was filtered and concentrated in vacuo to afford 6-(2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (16.0 g, 86% yield) as white Obtained as a solid.

[0188] Step 2: Synthesis of 7-chloro-6-(2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine

[0189] To a solution of 6-(2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (3.0 g, 26.4 mmol) in CH ₃ CN (80 mL) was added POCl ₃ (80 mL). The mixture was stirred at 100 °C for 16 hours. The mixture was concentrated in vacuo to give 7-chloro-6-(2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine (8.0 g, crude, 86% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 322.0

Step 3: Synthesis of 2-((6-(2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol

[0191] A solution of 7-chloro-6-(2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine (8.0 g, 24.8 mmol) and 2-aminoethanol (20 mL) was stirred at 90 °C for 2 h under N ₂ . The mixture was poured into water (100 mL) and filtered to give 2-((6-(2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (8.0 g, 93% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 347.1.

[0192] Step 4: Synthesis of 6-(2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

_Tekl . The reaction mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was concentrated, added dropwise to water, and stirred for 1 hour. The solid was filtered and concentrated in vacuo to afford 6-(2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (6.5 g, 86% yield) as a tan replacement. LCMS (M+H ⁺ ) m/z: 329.0.

[0194] Step 5: Synthesis of 6-(2-chlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0195] To a solution of 6-(2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (3.0 g, 9.15 mmol) in CH ₃ CN (50 mL) and H ₂ O (50 mL) was added Oxone (8.40 g, 13.7 mmol). The reaction mixture was stirred at 30° C. under N ₂ for 16 hours. The mixture was adjusted to pH = 7-8 with 1N NaOH aq, extracted with DCM (200 mL x 3), washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give crude 6-(2-chlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine which was further purified in the next step. used without. CMS (M+H ⁺ ) m/z: 361.0.

[0196] Step 6: Synthesis of tert-butyl 4-(4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate

[0197] To a solution of 6-(2-chlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (500 mg, 1.39 mmol) in DMSO (10 mL) was added tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (200 mg, 0. 68 mmol) was added. The reaction mixture was stirred at 120° C. for 1 hour under N ₂ . The mixture was poured into water, extracted with EtOAc (80 mL x 3), washed with brine (50 mL), dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography on silica gel (DCM/CH ₃ OH = 20:1) to yield tert-butyl 4-(4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3 Obtained -d]pyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (60 mg, 8% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 576.2

[0198] Step 7: Synthesis of 6-(2-chlorophenyl)-N-(3-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0199] To a solution of tert-butyl 4-(4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (60 mg, 0.10 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to give 6-(2-chlorophenyl)-N-(3-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 84% yield, TFA salt). Obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.85 (br, 1H), 10.24 (s, 1H), 9.07 (s, 1H), 8.93 (br, 2H), 8.30 (s, 1H), 7.80 (d, J = 14.4 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.62-7.51 (m, 4H), 7.15 (t, J = 9.6 Hz, 1H), 4.80-4.72 (m, 2H), 4.18-4.10 (m, 2H), 3.42-3.30 (m, 4H), 3.24-3.22 (m, 4H). LCMS (M+H ⁺ ) m/z: 476.1.

Example 12:6 -(2- chlorophenyl )-N-(2- Fluoro Preparation of -4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (Compound 12)

[0200] Step 1: Synthesis of tert-butyl 4-(4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate

[0201] To a solution of 6-(2-chlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (500 mg, 1.39 mmol) in DMSO (10 mL) was added tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (200 mg, 0. 68 mmol) was added. The reaction mixture was stirred at 120° C. for 1 hour under N ₂ . The mixture was poured into water, extracted with EtOAc (80 mL x 3), washed with brine (50 mL), dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography on silica gel (DCM/CH ₃ OH = 20:1) to yield tert-butyl 4-(4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3- Obtained d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (38 mg, 5% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 576.3.

[0202] Step 2: Synthesis of 6-(2-chlorophenyl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0203] To a solution of tert-butyl 4-(4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (38 mg, 0.10 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to give 6-(2-chlorophenyl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (15 mg, 50% yield, TFA salt). Obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.12 (br, 2H), 8.89-8.86 (m, 3H), 8.26 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.61-7.50 (m, 4H), 7.98 (d, J = 13.6 Hz, 1H), 6.87–6.85 (m, 1H), 4.07–4.04 (m, 2H), 3.70–3.62 (m, 2H), 3.46–3.40 (m, 4H), 3.32–3.26 (m, 4H). LCMS (M+H ⁺ ) m/z: 476.1.

Example 13: (3-((6-(2- chlorophenyl )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-yl)amino)phenyl)methanol (Compound 13)

[0204] Step 1: Synthesis of (3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)methanol

[0205] To 6-(2-chlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (80 mg, 0.22 mmol) in DMSO (2 mL) was added (3-aminophenyl)methanol (41 mg, 0.33 mmol). The reaction mixture was stirred in a microwave at 100 °C for 1 hour. The mixture was poured into water, extracted with EtOAc (20 mL x 3), washed with brine (10 mL), dried over Na ₂ SO ₄ , concentrated in vacuo and purified by preparative-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to yield (3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1’,2’:1,6]pyrido[2,3-d]pyrimi Obtained din-2-yl)amino)phenyl)methanol (8.2 mg, 10% yield, TFA salt) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.96 (s, 1H), 8.16 (s, 1H), 7.81-7.79 (m, 2H), 7.65-7.63 (m, 1H), 7.56-7.51 (m, 3H), 7.40-7.38 (m, 2H), 4. 63-4.60 (m, 4H), 4.18-4.16 (m, 2H). LCMS (M+H ⁺ ) m/z: 404.1.

Example 14:6 -(2- chlorophenyl )-N-(1- methyl -1H- pyrazole -5-day)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 14)

[0206] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(1-methyl-1H-pyrazol-5-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0207] To a solution of 6-(2-chlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 0.28 mmol) in DMSO (5 mL) was added 1-methyl-1H-pyrazol-5-amine (35 mg, 0.36 mmol). The reaction mixture was stirred in a microwave at 100 °C for 0.5 h. The mixture was poured into water, extracted with EtOAc (20 mL x 3), washed with (10 mL), concentrated in vacuo over Na ₂ SO ₄ then purified by preparative-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to yield 6-(2-chlorophenyl)-N-(1-methyl-1H-pyrazol-5-yl)-8,9-dihydroimidazo[1',2':1,6 Obtained ]pyrido[2,3-d]pyrimidin-2-amine (5.2 mg, 5% yield, TFA salt) as a yellow solid. ^1H NMR (400 MHz, CD ₃ OD): δ 9.33 (s, 1H), 8.94 (d, J = 4.0 Hz, 1H), 8.43 (s, 1H), 7.69-7.56 (m, 4H), 6.38 (d, J = 4.0 Hz, 1H), 4.93 (t, J = 10.0 Hz, 2H), 4.30 (t, J = 10.0 Hz, 2H), 4.19 (s, 3H). LCMS (M+H ⁺ ) m/z: 378.1.

Example 15:6 -(2- chlorophenyl )-N-(pyridin-3-yl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 15)

[0208] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(pyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0209] To a solution of 6-(2-chlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (60 mg, 0.17 mmol) in DMSO (2 mL) was added pyridin-3-amine (19 mg, 0.20 mmol). The reaction mixture was stirred in a microwave at 100 °C for 20 minutes. The mixture was poured into water, extracted with EtOAc (20 mL x 3), washed with (10 mL), dried over Na ₂ SO ₄ and concentrated in vacuo, then purified by preparative-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to yield 6-(2-chlorophenyl)-N-(pyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2, 3-d]pyrimidin-2-amine (4.2 mg, 7% yield, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 9.55 (s, 1H), 9.53 (s, 1H), 9.40 (d, J = 5.2 Hz, 1H), 8.54 (s, 1H), 7.98-7.97 (m, 2H), 7.71-7.57 (m, 4H), 5.05 (t, J = 10.0 Hz, 2H), 4.37 (t, J = 10.0 Hz, 2H). LCMS (M+H ⁺ ) m/z: 375.1.

Example 16:6 -(2- chlorophenyl )-N-(pyridin-4-yl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 16)

[0210] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0211] To a solution of 6-(2-chlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (60 mg, 0.17 mmol) in DMSO (2 mL) was added pyridin-4-amine (19 mg, 0.20 mmol). The reaction mixture was stirred in a microwave at 100 °C for 20 minutes. The mixture was poured into water, extracted with EtOAc (20 mL x 3), washed with (10 mL), dried over Na ₂ SO ₄ , concentrated in vacuo then purified by preparative-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to yield 6-(2-chlorophenyl)-N-(pyridin-4-yl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2 ,3-d]pyrimidin-2-amine (4.2 mg, 7% yield) was obtained as a yellow solid. ¹ H nmr (400 MHz, CD ₃ OD): δ 9.47 (s, 3h), 8.51 (s, 1h), 7.70-7.57 (m, 4h), 7.12 (D, J = J = 5.6 Hz, 2h), 5.05-5.02 (m, 2h), 4.37-4.34 (m, 2h). LCMS (M+H ⁺ ) m/z: 375.1.

Example 17:6 -(2- chlorophenyl )-N-(3- methoxyphenyl )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 17)

[0212] Step 1: Synthesis of 6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-ol

[0213] To a solution of 6-(2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (2.5 g, 7.62 mmol) in CH ₃ CN (35 mL) and H ₂ O (35 mL) was added Oxone (7.0 g, 11.4 mmol). The reaction mixture was stirred at 30° C. under N ₂ for 16 hours. The mixture was adjusted to pH = 8-9 with 1N NaOH aq and the solid was filtered to give 6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-ol (2.0 g, 93% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 299.1.

[0214] Step 2: Synthesis of 2-chloro-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0215] A solution of 6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-ol (2.0 g, 6.69 mmol) in POCl ₃ (30 mL) was stirred at 100 °C for 3 h. The mixture was concentrated in vacuo to afford 2-chloro-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (1.6 g, crude, 80% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 316.9.

[0216] Step 3: Synthesis of 6-(2-chlorophenyl)-N-(3-methoxyphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[ ₀₂₁₇ ] 2-chloro-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (0.2 g, 0.63 mmol) and 3-methoxyaniline (0.15 g, 1.26 mmol) and K ₂ CO ₃ (0.17 g, 1.26 mmol) in CH 3 CN (10 mL) The solution was stirred in a microwave at 150 °C for 30 minutes. The residue was concentrated in vacuo and then purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to afford 6-(2-chlorophenyl)-N-(3-methoxyphenyl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 20% yield, TFA salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.67 (br, 1H), 10.07 (br, 1H), 9.02 (s, 1H), 8.25 (s, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7. 61-7.50 (m, 3H), 6.98 (d, J = 8.8 Hz, 2H), 4.73-4.70 (m, 2H), 4.08-4.07 (m, 2H), 3.77 (s, 3H). LCMS (M+H ⁺ ) m/z: 404.1.

Example 18:6 -(2- chlorophenyl )-N-(3-( methylthio )phenyl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 18)

[0218] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(3-(methylthio)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0219] 2-chloro-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (0.2 g, 0.63 mmol) and 3-(methylthio)aniline (0.18 g, 1.26 mmol) and K ₂ CO ₃ (0.17 g, 1.26 mmol) in CH ₃ CN (10 mL) 6 mmol) was stirred in a microwave at 150 °C for 30 min. The residue was concentrated in vacuo and then purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to afford 6-(2-chlorophenyl)-N-(3-(methylthio)phenyl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 19% yield, TFA salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.99 (br, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 7.86 (s, 1H), 7.59-7.54 (m, 2H), 7.46-7.38 (m, 4H), 7.24 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 4.20 (t, J = 9.2 Hz, 2H), 3.97 (t, J = 9.2 Hz, 2H), 2.48 (s, 3H). LCMS (M+H ⁺ ) m/z: 420.4.

Example 19:6 -(2- chlorophenyl )-N-(4- fluorophenyls )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 19)

[0220] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(4-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[ ₀₂₂₁ ] 2-chloro-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (0.2 g, 0.63 mmol) and 4-fluoroaniline (0.14 g, 1.26 mmol) and K ₂ CO ₃ (0.17 g, 1.26 mmol) in CH 3 CN (10 mL) The solution was stirred in a microwave at 150 °C for 30 minutes. The residue was concentrated in vacuo and then purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to afford 6-(2-chlorophenyl)-N-(4-fluorophenyl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (30 mg, 15% yield, TFA salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.81 (br s, 1H), 10.18 (br s, 1H), 9.08 (s, 1H), 8.89 (s, 1H), 7.97-7.81 (m, 2H), 7.71-7.67 (m, 1H), 7.61 −7.52 (m, 3H), 7.24 (t, J = 8.8 Hz, 2H), 4.75–4.72 (m, 2H), 4.03–4.00 (m, 2H). LCMS (M+H ⁺ ) m/z: 392.0.

Example 20:6 -(2- chlorophenyl )-N-(3- Fluoro -4- methylphenyl )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 20)

[0222] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(3-fluoro-4-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0223] 2-chloro-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (0.2 g, 0.63 mmol) and 3-fluoro-4-methylaniline (0.24 g, 1.26 mmol) and K ₂ CO ₃ (0.17 g, 1.26 mmol) in CH ₃ CN (10 mL). 26 mmol) was stirred in a microwave at 150° C. for 30 min. The residue was concentrated in vacuo and then purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to afford 6-(2-chlorophenyl)-N-(3-fluoro-4-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (20 mg, 15% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.99 (s, 1H), 8.40 (s, 1H), 7.80 (dd, J = 8.8, 2.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.45-7.39 (m, 4H), 7.38 (s, 1H), 7.18 (t, J = 8.8 Hz, 1H), 4.16–4.11 (m, 2H), 3.98–3.94 (m, 2H), 2.18 (s, 3H). LCMS (M+H ⁺ ) m/z: 406.1.

Example 21:6 -(2- chlorophenyl )-N-( oxetane -3-day)-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-amine (Compound 21)

[0224] Step 1: 6-(2-chlorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0225] To a mixture of 2-chloro-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (150 mg, 0.47 mmol), oxetan-3-amine (186 mg, 2.36 mmol) in CH ₃ CN (5 mL) was added K ₂ CO ₃ (0.325 g, 2.36 mmol) ) was added and then stirred in a microwave at 150°C for 0.5 hour. The reaction mixture was concentrated in vacuo to remove the solvent and then purified by prep-HPLC (0.1% NH ₃ HCl) to give 6-(2-chlorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (6.4 mg, 5% yield) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.25 (s, 1H), 7.48-7.47 (m, 1H), 7.37-7.36 (m, 3H), 7.24 (s, 1H), 5.13-5.08 (m, 2H), 4.76-4.68 (m, 3H), 4. 20 (t, J = 9.6 Hz, 2H), 4.00 (t, J = 9.6 Hz, 2H). LCMS (M+H ⁺ ) m/z: 354.0.

Example 22:6 -(2- chlorophenyl )-N-(4-(2-(dimethylamino) ethoxy )phenyl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 22)

[0226] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(4-(2-(dimethylamino)ethoxy)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0227] A solution of 4-(2-(dimethylamino)ethoxy)aniline (60 mg, 0.31 mmol), TFA (0.5 mL) and 2-chloro-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 0.31 mmol) in iPrOH (5 mL) was added to an 80 It was stirred for 6 hours at °C. The mixture was then diluted with water (30 mL) then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (30 mL x 2) and brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The mixture was purified on preparative-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to afford 6-(2-chlorophenyl)-N-(4-(2-(dimethylamino)ethoxy)phenyl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (2.8 mg, 2% yield, TFA salt) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.94 (s, 1H), 8.14 (s, 1H), 7.80-7.76 (m, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.56-7.51 (m, 3H), 7.09-7.07 (m, 2H), 4.87-4.85 (m, 2H), 4.37-4.35 (m, 2H), 4.19-4.15 (m, 2H), 3.62-3.60 (m, 2H), 3.00 (s, 6H). LCMS (M+H ⁺ ) m/z: 461.2.

Example 23:1 -(3- Chloro -4-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)-3-methylimidazolidin-2-one (Compound 23)

[0228] Step 1: Synthesis of 2-(4-bromo-2-chlorophenyl)acetonitrile

[0229] To a solution of 4-bromo-1-(bromomethyl)-2-chlorobenzene (10.0 g, 35.6 mmol) and TBAB (1.05 g, 3.26 mmol) in DCM (37.5 mL) and water (37.5 mL) was added NaCN (2.43 g, 49.6 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was extracted with EtOAc (50 mL x 3), washed with brine (500 mL), then dried over Na ₂ SO ₄ and purified by column chromatography on silica gel (PE/EtOAc = 2:1) to give 2-(4-bromo-2-chlorophenyl)acetonitrile (7.4 g, 90% yield) as a white solid.

[0230] Step 2: Synthesis of methyl 2-(4-bromo-2-chlorophenyl)acetate

[0231] SOCl ₂ (37 mL) was added dropwise to a solution of 2-(4-bromo-2-chlorophenyl)acetonitrile (7.4 g, 32 mmol) in MeOH (75 mL) at 0 °C. The mixture was stirred overnight at room temperature. The solvent was then removed and extracted with EtOAc (50 mL x 3), washed with brine (500 mL), dried over Na ₂ SO ₄ , concentrated and then purified by column chromatography on silica gel (PE/EtOAc = 4:1) to give methyl 2-(4-bromo-2-chlorophenyl)acetate (7.5 g, 84% yield) as a colorless oil. LCMS (M+H ⁺ ) m/z: 262.9.

[0232] Step 3: Synthesis of 6-(4-bromo-2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0233] NMP (60 mL) methyl 2- (4-bromo-2-chlorophenyl) acetate (6.0 g, 22.9 mmol), 4-amino-2- (methylthio) pyrimidine-5-carvaldehyde (3.8 g, 22.9 mmol) and K ₂ CO ₃ (6.3 g, 46 mmol) solution It was stirred for 16 hours under n ₂ at ° C. The mixture was poured into water and filtered to give 6-(4-bromo-2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (6.6 g, 75% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 381.9.

[0234] Step 4: 6-(4-Bromo-2-chlorophenyl)-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine

[0235] A solution of 6-(4-bromo-2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (6.6 g, 17.4 mmol) in POCl ₃ (10 mL) and CH ₃ CN (30 mL) was stirred at 90 °C for 2 h. Removal of the solvent gave crude 6-(4-bromo-2-chlorophenyl)-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (6.0 g, 86% yield) as a yellow oil. LCMS (M+H ⁺ ) m/z: 400.2.

[0236] Step 5: Synthesis of 2-((6-(4-bromo-2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol

[0237] To a solution of 6-(4-bromo-2-chlorophenyl)-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (6.0 g, 15 mmol) in iPrOH (5 mL) was added 2-aminoethanol (5 mL). The reaction mixture was stirred at 80° C. under N ₂ for 16 hours. The mixture was filtered to give 2-((6-(4-bromo-2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (3.8 g, 60% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 425.0.

[0238] Step 6: Synthesis of 6-(4-bromo-2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0239] To a solution of 2-((6-(4-bromo-2-chlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (3.8 g, 8.9 mmol) and Et ₃ N (1.8 g, 18 mmol) in DCM (5 mL) was added MsCl (2 g, 18 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed and purified by column chromatography on silica gel (DCM/MeOH = 20:1) to give 6-(4-bromo-2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (2.5 g, 69% yield) as a yellow solid. LCMS (MH ⁺ ) m/z: 407.1.

[0240] Step 7: Synthesis of 6-(4-bromo-2-chlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0241] To a solution of 6-(4-bromo-2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (1.3 g, 3.2 mmol) in CH ₃ CN (15 mL) and water (15 mL) was added Oxone (4.0 g, 6.4 mmol). The reaction mixture was stirred at room temperature under N ₂ for 48 hours. The mixture was extracted with EtOAc (30 mL x 3), washed with NH ₄ Cl aq (50 mL) and brine (50 mL), then dried over Na ₂ SO ₄ and concentrated in vacuo to give 6-(4-bromo-2-chlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (800 mg, 57 % yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 439.0.

[0242] Step 8: Synthesis of 6-(4-bromo-2-chlorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0243] To a solution of 6-(4-bromo-2-chlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (800 mg, 1.8 mmol) in THF (8 mL) was added CH ₃ NH ₂ in THF (5 mL). The mixture was stirred at 50° C. under N ₂ for 2 h. The mixture was concentrated in vacuo to afford 6-(4-bromo-2-chlorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (650 mg, 92% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 390.0.

[0244] Step 9: 1-(3-chloro-4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d Synthesis of ]pyrimidin-6-yl)phenyl)-3-methylimidazolidin-2-one

[0245] 6-(4-bromo-2-chlorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (20 mg, 0.05 mmol), 1-methylimidazolidin-2-one (10 mg, 0.1 mmol), Pd ₂ (dba) ₃ (4 in dioxane (2 mL)) .5 mg, 0.005 mmol), Xantphos (5.8 mg, 0.01 mmol), and Cs ₂ CO ₃ (32.5 mg, 0.1 mmol) were stirred at 120° C. under N ₂ for 2 h under microwave irradiation. The mixture was concentrated in vacuo and then purified by preparative-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to yield 1-(3-chloro-4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-methylimidazolidin-2-one (5 mg, 25% yield, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.88-8.77 (m, 1H), 8.05 (s, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.4, 2.0 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 4.76-4.70 (m, 2H), 4.15 (t, J = 9.2 Hz, 2H), 3.90 (t, J = 8.0 Hz, 2H), 3.57 (t, J = 8.0 Hz, 2H), 3.07 (s, 3H), 2.89 (s, 3H). LCMS (M+H ⁺ ) m/z: 410.2.

Example 24:1 -(3- Chloro -4-(2-( ethylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)-3-methylpyrazin-2(1H)-one (Compound 24)

[0246] Step 1: Synthesis of 1-(3-chloro-4-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-methylpyrazin-2(1H)-one

[0247] 6-(4-Bromo-2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 0.24 mmol), 3-methylpyrazin-2(1H)-one (50 mg, 0.48 mmol), CuI (10 mg, 0 .048 mmol), K ₃ PO ₄ (194 mg, 0.72 mmol) and N ¹ ,N ² -dimethylethane-1,2-diamine (8.4 mg, 0.096 mmol) was stirred at 110° C. under N ₂ for 18 h. After concentrating the mixture of the mixture, the column chromatography (dcm/meoh = 10: 1) on the silica gel and purified by the column chromatography (dcm/meoh = 10: 1) and 1- (3-chloro-4- (2- (2- (methylthio) -8,9-dihydo) already '1', 2 ': 1,6] flute [2,3-d] pyrimidine-6-yl) ) -On (10 mg, 10% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 437.1.

[0248] Step 2: Synthesis of 1-(3-chloro-4-(2-(ethylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-methylpyrazin-2(1H)-one

[0249] 1-(3-chloro-4-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2, To a solution of 3-d]pyrimidin-6-yl)phenyl)-3-methylpyrazin-2(1H)-one (10 mg, 0.022 mmol) was added m-CPBA (10 mg, 0.057 mmol). The mixture was stirred at room temperature under N ₂ for 2 hours. Then EtNH ₂ in THF (1 mL) was added and the mixture was stirred at 50° C. for 2 h. The mixture was concentrated in vacuo and then purified by prep-HPLC (0.1% TFA/CH ₃ CN/H ₂ O) to yield 1-(3-chloro-4-(2-(ethylamino)-8,9-dihydroimine Dazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-methylpyrazin-2(1H)-one (3.0 mg, 30% yield, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.90-8.82 (m, 1H), 8.14 (s, 1H), 7.85 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.62 ( d, J = 8.0 Hz, 1H), 7.46 (d, J = 4.4 Hz, 1H), 7.34 (d, J = 4.4 Hz, 1H), 4.79–4.77 (m, 2H), 4.18–4.15 (m, 2H) ), 3.60–3.55 (m, 2H), 2.46 (s, 3H), 1.32–1.24 (m, 3H). LCMS (M+H ⁺ ) m/z: 434.1.

Example 25:6 -(2- Chloro -4-(6- Methylpyrazine -2-yl) phenyl) -N- methyl -8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 25)

[0250] Step 1: Synthesis of methyl 2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

[0251] Methyl 2-(4-bromo-2-chlorophenyl)acetate (2.0 g, 7.6 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.13 g, 8.38 mmol), Pd(dppf)Cl ₂ (500 mg) in dioxane (20 mL) , 0.68 mmol) and KOAc (2.2 g, 22.4 mmol) were stirred at 80 °C for 4 h. The mixture was extracted with EtOAc (50 mL x 3), washed with brine (500 mL), then dried over Na ₂ SO ₄ and purified by column chromatography on silica gel (PE/EtOAc = 20:1) to give methyl 2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (2.0 g, 84% yield) ) was obtained as a white solid. LCMS (M+H ⁺ ) m/z: 311.4.

[0252] Step 2: Synthesis of methyl 2-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)acetate

[0253] Methyl 2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.7 g, 5.5 mmol), 2-chloro-6-methylpyrazine (650 mg, 5.0 mmol), Pd(PPh ₃ ) ₄ (557 mg, 0.5 mmol) and Na ₂ CO ₃ (1.06 g, 10 mmol) was stirred at 85 °C for 18 h. The mixture was extracted with EtOAc (50 mL x 3), washed with brine (500 mL), dried over Na ₂ SO ₄ and purified by column chromatography on silica gel (PE/EtOAc = 20:1) to give methyl 2-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)acetate (600 mg, 40% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 277.1.

[0254] Step 3: Synthesis of 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0255] A solution of methyl 2-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)acetate (600 mg, 2.17 mmol), 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (366 mg, 2.17 mmol) and K ₂ CO ₃ (603 mg, 4.34 mmol) in NMP (10 mL) at 110 °C Stirred under N ₂ for 16 hours. The mixture was poured into water and filtered to give 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (300 mg, 35% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 396.1.

[0256] Step 4: 7-Chloro-6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine

[0257] A solution of 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (300 mg, 0.76 mmol) in POCl ₃ (2 mL) and CH ₃ CN (6 mL) was stirred at 90 °C for 2 h. Removal of the solvent gave crude 7-chloro-6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine (270 mg, 86% yield) as a yellow oil. LCMS (M+H ⁺ ) m/z: 414.1.

[0258] Step 5: Synthesis of 2-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethane-1-ol

[0259] To a solution of 7-chloro-6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine (250 mg, 0.60 mmol) in i-PrOH (5 mL) was added 2-aminoethanol (0.5 mL). The reaction mixture was stirred at 80° C. under N ₂ for 16 hours. The mixture was filtered to give 2-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (200 mg, 76% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 439.2.

[0260] Step 6: Synthesis of 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0261] _MsCl (26 mg, 0.22 mg, 0.22 8 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed and purified by column chromatography on silica gel (DCM/MeOH = 20:1) to give 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (40 mg, 83% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 421.1.

[0262] Step 7: Synthesis of 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0263] To a solution of 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (20 mg, 0.047 mmol) in THF (2 mL) was added m-CPBA (19 mg, 0.095 mmol). The reaction mixture was stirred at room temperature under N ₂ for 20 minutes. Removal of the solvent gave crude 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (20 mg, 90% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 453.1.

[0264] Step 8: Synthesis of 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0265] To a solution of 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (20 mg, 0.044 mmol) in THF (8 mL) was added CH ₃ NH ₂ in THF (5 mL). The mixture was incubated at room temperature under N ₂ for 0.5 h. The mixture was concentrated in vacuo and then purified by preparative-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to afford 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (8 mg, 40% yield, TFA salt) as a yellow solid. obtained. ^1H NMR (400 MHz, CD ₃ OD): δ 9.00 (s, 1H), 8.92-8.81 (m, 1H), 8.53 (s, 1H), 8.38 (d, J = 1.6 Hz, 1H), 8.20 (dd, J = 8.0, 1.6 Hz, 1H), 8.16 (s, 1 H), 7.64 (d, J = 8.0 Hz, 1H), 4.81–4.78 (m, 2H), 4.17–4.15 (m, 2H), 3.08 (s, 3H), 2.66 (s, 3H). LCMS (M+H ⁺ ) m/z: 404.1.

Example 26:6 -(4- chlorophenyl )-N-(3- Fluoro Preparation of -4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (Compound 26)

[0266] Step 1: Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-ol

[0267] To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7-ol (8.0 g, 41.45 mmol) in DMF (200 mL) was added NBS (7.75 g, 43.52 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and stirred for 1 hour. The solid was filtered and concentrated in vacuo to give 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-ol (9.6 g, 85% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 272.0

[0268] Step 2: Synthesis of 6-bromo-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine

[0269] To a solution of CH ₃ CN (100 mL) was added 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-ol (9.6 g, 35.3 mmol) POCl ₃ (100 mL). The mixture was stirred at 100 °C for 16 hours. The mixture was concentrated in vacuo to give 6-bromo-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (9.8 g, crude, 86% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 289.9

[0270] Step 3: Synthesis of 2-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol

[0271] A solution of 6-bromo-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (5.1 g, 17.59 mmol) and 2-aminoethanol (10 mL) was stirred at 90 °C for 2 h under N ₂ . The mixture was poured into water (100 mL) and filtered to give 2-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (4.2 g, 76% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 315.0

[0272] Step 4: Synthesis of 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0273] To a solution of 2-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (4.2 g, 13.3 mmol) and Et ₃ N (4.03 g, 39.9 mmol) in DCM (100 mL) was added MsCl (3.1 g, 26.6 mmol). The reaction mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was extracted with DCM (60 mL x 3), washed with brine (30 mL), dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography on silica gel (DCM/CH ₃ OH = 60:1) to give 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (2.3 g, 59 % yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 297.0.

[0274] Step 5: Synthesis of 6-bromo-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0275] To a solution of 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (1.2 g, 4.04 mmol) in CH ₃ CN (50 mL) and H ₂ O (50 mL) was added Oxone (3.70 g, 6.06 mmol). The reaction mixture was stirred at 30° C. under N ₂ for 16 hours. The mixture was adjusted to pH = 7-8 with 1N NaOH aq, extracted with DCM (100 mL x 3), washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give crude 6-bromo-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine which was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 329.0.

[0276] Step 6: Synthesis of tert-butyl 4-(4-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate

[0277] To a solution of 6-bromo-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (360 mg, 1.09 mmol) in DMSO (10 mL) tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (324 mg, 1.09 mmol) was added. The reaction mixture was stirred at 120° C. for 1 hour under N ₂ . The mixture was added to water, extracted with EtOAc (80 mL x 3), washed with brine (30 mL), dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography on silica gel (DCM/CH ₃ OH = 20:1) to yield tert-butyl 4-(4-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] Obtained pyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (130 mg, 22% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 544.1

[0278] Step 7: Synthesis of tert-butyl 4-(4-((6-(4-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate

[0279] 디옥산/H ₂ O (10 mL, v/v = 5/1) 중 tert-부틸 4-(4-((6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)아미노)-2-플루오로페닐)피페라진-1-카르복실레이트 (60 mg, 0.11 mmol), (4-클로로페닐)보론산 (52 mg, 0.33 mmol), Pd(dppf)Cl ₂ .DCM (10.0 mg, 0.01 mmol) 및 Na ₂ CO ₃ (23 mg, 0.22 mmol)의 혼합물을 실온에서 퍼징하고 N ₂ 에서 3회 탈기한 다음, 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated. The solvent was removed and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to obtain tert-butyl 4-(4-((6-(4-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (45 mg , 71% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 576.3.

[0280] Step 8: Synthesis of 6-(4-chlorophenyl)-N-(3-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0281] To a solution of tert-butyl 4-(4-((6-(4-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (45 mg, 0.078 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and then purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to give 6-(4-chlorophenyl)-N-(3-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (20 mg, 50% yield, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.79 (br, 1H), 10.26 (br, 1H), 9.05 (s, 1H), 8.90 (br, 2H), 8.30 (s, 1H), 8.80 (d, J = 14.0 Hz, 1H), 7.68-7.56 (m, 5H), 7.14 (t, J = 9.6 Hz, 1H), 4.69–4.64 (m, 2H), 4.13–4.08 (m, 2H), 3.46–3.42 (m, 4H), 3.20–3.15 (m, 4H). LCMS (M+H ⁺ ) m/z: 476.1.

Example 27: N-(3- Fluoro -4-(piperazin-1-yl)phenyl)-6-phenyl-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 27)

[0282] Step 1: Synthesis of tert-butyl 4-(2-fluoro-4-((6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

[0283] 디옥산/H ₂ O (10 mL, v/v = 5/1) 중 tert-부틸 4-(4-((6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)아미노)-2-플루오로페닐)피페라진-1-카르복실레이트 (60 mg, 0.11 mmol), 페닐보론산 (40 mg, 0.33 mmol), Pd(dppf)Cl ₂ .DCM (18.0 mg, 0.02 mmol) 및 Na ₂ CO ₃ (35 mg, 0.33 mmol)의 혼합물을 실온에서 퍼징하고 N ₂ 로 3회 탈기시킨 다음, 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated, the solvent was removed and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to give tert-butyl 4-(2-fluoro-4-((6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (40 mg, 62 % yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 542.4.

[0284] Step 2: Synthesis of N-(3-fluoro-4-(piperazin-1-yl)phenyl)-6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0285] To a solution of tert-butyl 4-(2-fluoro-4-((6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (40 mg, 0.07 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and then purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to afford N-(3-fluoro-4-(piperazin-1-yl)phenyl)-6-phenyl-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (20 mg, 61% yield, TFA salt) as a yellow solid. . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.99 (s, 1H), 8.19 (s, 1H), 7.86-7.82 (m, 1H), 7.58-7.48 (m, 6H), 7.13 (t, J = 8.8 Hz, 1H), 4.83-4.80 (m, 2H), 4.23-4.18 (m, 2H), 3.42-3.39 (m, 4H), 3.33-3.30 (m, 4H). LCMS (M+H ⁺ ) m/z: 442.1.

Example 28:6 -(4- chlorophenyl )-N-(2- Fluoro Preparation of -4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (Compound 28)

[0286] Step 1: Synthesis of tert-butyl 4-(4-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate

[0287] To a solution of 6-bromo-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (700 mg, 2.13 mmol) in DMSO (20 mL) tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (600 mg, 2.02 mmol) was added. The reaction mixture was stirred at 120° C. for 1 hour under N ₂ . The mixture was added to water, extracted with EtOAc (80 mL x 3), washed with brine (30 mL), dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography on silica gel (DCM/CH ₃ OH = 60:1) to yield tert-butyl 4-(4-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d Obtained ]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (300 mg, 25% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 544.1

[0288] Step 2: Synthesis of tert-butyl 4-(4-((6-(4-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate

[0289] tert- _butyl 4-(4-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (60 mg, 0.11 mmol), (4- A mixture of chlorophenyl)boronic acid (52 mg, 0.33 mmol), Pd(dppf)Cl ₂ .DCM (10.0 mg, 0.01 mmol) and Na ₂ CO ₃ (23 mg, 0.22 mmol) was purged at room temperature, degassed with N ₂ 3 times and then stirred at 100° C. for 16 hours. The reaction mixture was concentrated to remove the solvent and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to obtain tert-butyl 4-(4-((6-(4-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (30 mg, 71% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 576.3.

[0290] Step 3: Synthesis of 6-(4-chlorophenyl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0291] To a solution of tert-butyl 4-(4-((6-(4-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (30 mg, 0.05 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and then purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to give 6-(4-chlorophenyl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (11 mg, 48% yield, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.93 (br, 1H), 8.19 (s, 1H), 7.80 (br, 1H), 7.59-7.54 (m, 4H), 6.96-6.89 (m, 2H), 4.86-4.66 (m, 2H), 4.17-4. 13 (m, 2H), 3.47–3.40 (m, 4H), 3.38–3.30 (m, 4H). LCMS (M+H ⁺ ) m/z: 476.1.

Example 29: N-(2- Fluoro -4-(piperazin-1-yl)phenyl)-6-phenyl-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 29)

[0292] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-((6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

[0293] 디옥산/H ₂ O (10 mL, v/v = 5/1) 중 tert-부틸 4-(4-((6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)아미노)-3-플루오로페닐)피페라진-1-카르복실레이트 (60 mg, 0.11 mmol), 페닐보론산 (48 mg, 0.33 mmol), Pd(dppf)Cl ₂ .DCM (20.0 mg, 0.02 mmol) 및 Na ₂ CO ₃ (23 mg, 0.22 mmol)의 혼합물을 실온에서 퍼징하고 N ₂ 로 3회 탈기한 다음, 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated to remove the solvent and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to yield tert-butyl 4-(3-fluoro-4-((6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (35 mg, 50% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 542.3.

[0294] Step 2: Synthesis of N-(2-fluoro-4-(piperazin-1-yl)phenyl)-6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0295] To a solution of tert-butyl 4-(3-fluoro-4-((6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (35 mg, 0.06 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and then purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to afford N-(2-fluoro-4-(piperazin-1-yl)phenyl)-6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (15 mg, 58% yield, TFA salt) as a yellow solid. . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.93 (br, 1H), 8.17 (s, 1H), 7.80 (br, 1H), 7.57-7.52 (m, 5H), 6.86-6.71 (m, 2H), 4.86-4.71 (m, 2H), 4.17-4. 12 (m, 2H), 3.47–3.45 (m, 4H), 3.40–3.38 (m, 4H). LCMS (M+H ⁺ ) m/z: 442.2.

Example 30: N-(2- Fluoro -4-(piperazin-1-yl)phenyl)-6-(o- Tolil )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 30)

[0296] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-((6-(o-tolyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

[0297] 디옥산/H ₂ O (10 mL, v/v = 5/1) 중 tert-부틸 4-(4-((6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)아미노)-3-플루오로페닐)피페라진-1-카르복실레이트 (60 mg, 0.11 mmol), o-톨릴보론산 (45 mg, 0.33 mmol), Pd(dppf)Cl ₂ .DCM (16.0 mg, 0.02 mmol) 및 Na ₂ CO ₃ (23 mg, 0.22 mmol)의 혼합물을 실온에서 퍼징하고 N ₂ 로 3회 탈기한 다음, 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated to remove the solvent and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to give tert-butyl 4-(3-fluoro-4-((6-(o-tolyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (35 mg, 57% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 556.4.

[0298] Step 2: Synthesis of N-(2-fluoro-4-(piperazin-1-yl)phenyl)-6-(o-tolyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0299] To a solution of tert-butyl 4-(3-fluoro-4-((6-(o-tolyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (35 mg, 0.06 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to afford N-(2-fluoro-4-(piperazin-1-yl)phenyl)-6-(o-tolyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (16 mg, 56% yield, TFA salt). Obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.03 (br, 2H), 8.92 (br, 3H), 8.06 (br, 1H), 7.43-7.39 (m, 3H), 7.35 (t, J = 7.2 Hz, 1H), 7.28 (dd, J = 7.2 Hz, 1H), 6.97 (dd, J = 13.6, 2.4 Hz, 1H), 6.85 (dd, J = 8.8, 2.4 Hz, 1H), 4.50-4.47 (m, 2H), 4.01-3.99 (m, 2H), 3.42-3.39 (m, 4H), 3.25-3.23 (m, 4H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 456.2.

Example 31: N-(2- Fluoro -4-(piperazin-1-yl)phenyl)-6-(2- methoxyphenyl Preparation of )-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (Compound 31)

[0300] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-((6-(2-methoxyphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

[0301] 디옥산/H ₂ O (10 mL, v/v = 5/1) 중 tert-부틸 4-(4-((6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)아미노)-3-플루오로페닐)피페라진-1-카르복실레이트 (60 mg, 0.11 mmol), (2-메톡시페닐)보론산 (50 mg, 0.33 mmol), Pd(dppf)Cl ₂ .DCM (16.0 mg, 0.02 mmol) 및 Na ₂ CO ₃ (23 mg, 0.22 mmol)의 혼합물을 실온에서 퍼징하고 N ₂ 로 3회 탈기한 다음, 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated to remove the solvent and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to obtain tert-butyl 4-(3-fluoro-4-((6-(2-methoxyphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (35 mg, 58% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 572.3.

[0302] Step 2: Synthesis of N-(2-fluoro-4-(piperazin-1-yl)phenyl)-6-(2-methoxyphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0303] Tert-butyl 4- (3-fluoro-4-(6- (2-methoxyphenyl)-(2-methoxyphenyl)-(2-metoxyphenyl)-(2 '1', 2 ': 1,6] pyrimidin-2-yl) phenyl) Piperazine-1-carboxylate (35 mg, 0.06 mmol) TFA (2 mL) was added to the solution of. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and then purified by preparative-HPLC (0.1% TFA, CH ₃ CN in H ₂ O)fhh to obtain N-(2-fluoro-4-(piperazin-1-yl)phenyl)-6-(2-methoxyphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (23 mg, 56% yield, T FA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.12 (br, 1H), 9.87 (br, 1H), 8.97-8.90 (m, 3H), 8.18 (s, 1H), 7.55-7.51 (m, 1H), 7.34 (dd, J = 7.6, 1.6 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.98 (dd, J = 13.6, 1.6 Hz, 1H), 6.85 (dd, J = 8.4, 2.0 Hz, 1H), 4.51-4.49 (m, 2H), 4.05-3.99 (m, 2H), 3.81 (s, 3H), 3.42-3.39 (m, 4H), 3.25-3.23 (m, 4H). LCMS (M+H ⁺ ) m/z: 472.2.

Example 32: N-(2- Fluoro -4-(piperazin-1-yl)phenyl)-6-(pyridin-2-yl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 32)

[0304] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-((6-(pyridin-2-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

[0305] tert-butyl 4-(4-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (60 mg, 0.11 mmol), 2-(tributylstannyl)pyridine (122 mg) in dioxane (10 mL) , 0.33 mmol), Pd(PPh ₃ ) ₂ Cl ₂ . (16.0 mg, 0.023 mmol) was purged at room temperature and degassed with N ₂ three times, then stirred at 100° C. for 16 hours. The reaction mixture was concentrated to remove the solvent and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to obtain tert-butyl 4-(3-fluoro-4-((6-(pyridin-2-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (30 mg, 35% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 543.3.

[0306] Step 2: Synthesis of N-(2-fluoro-4-(piperazin-1-yl)phenyl)-6-(pyridin-2-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0307] Tert-butyl 4- (3-fluoro-4-(6- (pyridine-2-yl)-(pyridine-2-yl)-(pyridine-2-yl)-(2 '1', 2 ': 1,6] pyrimidine-2-yl) phenyl) piperazine-1-carboxylate (38 mg, 0.07 mmol) TFA (2 mL) was added to the solution of the solution. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to give N-(2-fluoro-4-(piperazin-1-yl)phenyl)-6-(pyridin-2-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (12 mg, 37% yield, TFA salt ) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.96-10.83 (m, 1H), 10.30-10.25 (m, 1H), 9.08 (s, 1H), 9.07-8.92 (m, 3H), 8.70 (d, J = 4.0 Hz, 1H), 8.17 (d ; 3.50-3.46 (m, 4H), 3.41-3.39 (m, 4H). LCMS (M+H ⁺ ) m/z: 443.2.

Example 33: N-(2- Fluoro -4-(piperazin-1-yl)phenyl)-6-(thiazol-4-yl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 33)

[0308] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-((6-(thiazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

[0309] 디옥산/H ₂ O (10 mL, v/v = 5/1) 중 tert-부틸 4-(4-((6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)아미노)-3-플루오로페닐)피페라진-1-카르복실레이트 (50 mg, 0.10 mmol), 티아졸-4-일보론산 (30 mg, 0.32 mmol), Pd(dppf)Cl ₂ .DCM (18.0 mg, 0.02 mmol) 및 Na ₂ CO ₃ (35 mg, 0.33 mmol)의 혼합물을 실온에서 퍼징하고 N ₂ 로 3회 탈기한 다음 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated to remove the solvent and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to yield tert-butyl 4-(3-fluoro-4-((6-(thiazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (3 0 mg, 20% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 549.2.

Step 2: Synthesis of N-(2-fluoro-4-(piperazin-1-yl)phenyl)-6-(thiazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0311] Tert-butyl 4- (3-fluoro-4- (6- (thiazol-4-yl)-(thiazol-4-yl)-(1 '1', 2 ': 1,6] pyrimidine-2-yl) phenyl) piperazine-1-carboxylate (30 mg, 0.06 mmol) TFA (2 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to give N-(2-fluoro-4-(piperazin-1-yl)phenyl)-6-(thiazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (8 mg, 25% yield, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 9.20 (s, 1H), 8.96 (br, 1H), 8.77 (s, 1H), 8.27 (s, 1H), 7.86 (br, 1H), 6.96-6.89 (m, 2H), 4.88-4.68 (m, 2H), 4.30-4.25 (m, 2H), 3.48-3.45 (m, 4H), 3.40-3.30 (m, 4H). LCMS (M+H ⁺ ) m/z: 449.1.

Example 34: N-(2- Fluoro -4-(piperazin-1-yl)phenyl)-6-(pyridin-4-yl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 34)

[0312] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-((6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

[0313] tert-butyl 4-(4-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (60 mg, 0.11 mmol), 4-(tributylstannyl)pyridine (122 mg) in dioxane (10 mL) , 0.33 mmol), Pd(PPh ₃ ) ₂ Cl ₂ . (16.0 mg, 0.023 mmol) was purged at room temperature, degassed 3 times with N ₂ and stirred at 100° C. for 16 hours. The reaction mixture was concentrated to remove the solvent and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to yield tert-butyl 4-(3-fluoro-4-((6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (15 mg, 15% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 543.2.

[0314] Step 2: Synthesis of N-(2-fluoro-4-(piperazin-1-yl)phenyl)-6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0315] Tert-butyl 4- (3-fluoro-4-(6- (pyridine-4-yl)-(pyridine-4-yl)-(pyridine-4-yl)-(2 '1', 2 ': 1,6] pyrimidine-2-yl) phenyl) piperazine-1-carboxylate (15 mg, 0.03 mmol) TFA (2 mL) was added to the solution of. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to give N-(2-fluoro-4-(piperazin-1-yl)phenyl)-6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (12 mg, 30% yield, TFA salt ) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.99 (s, 1H), 8.87 (s, 2H), 8.41 (s, 1H), 7.87-7.85 (m, 3H), 6.96-6.89 (m, 2H), 4.72-4.65 (m, 2H), 4.19-4. 16 (m, 2H), 3.48–3.46 (m, 4H), 3.40–3.37 (m, 4H). LCMS (M+H ⁺ ) m/z: 443.2.

Example 35:6 -(2,4- dichlorophenyl )-N-(2- methoxy -6-(piperazin-1-yl)pyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (compound 35) manufacturing

[0316] Step 1: Synthesis of tert-butyl 4-(5-((6-(2,4-dichlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate

[0317] To a solution of 6-(2,4-dichlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (80 mg, 0.20 mmol) in DMSO (3 mL) was added tert-butyl 4-(5-amino-6-methoxypyridin-2-yl)piperazine-1-carboxylate (6 2 mg, 0.20 mmol) was added. The reaction mixture was stirred at 120° C. for 2 h under N ₂ . The mixture was poured into water, extracted with EtOAc (10 mL x 3), washed with brine (50 mL), dried over Na ₂ SO ₄ , concentrated and purified by preparative-TLC (EtOAc) to yield tert-butyl 4-(5-((6-(2,4-dichlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine- Obtained 2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate (25 mg, 19% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 623.3.

[0318] Step 2: Synthesis of 6-(2,4-dichlorophenyl)-N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0319] To a solution of tert-butyl 4-(5-((6-(2,4-dichlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate (25 mg, 0.040 mmol) in MeOH (1 mL), HCl /Dioxane (2 mL, 3M) was added. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated and purified by prep-HPLC (0.1% TFA/CH ₃ CN/H ₂ O) to give 6-(2,4-dichlorophenyl)-N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (13.4 mg, 5 0% yield, TFA salt) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.99-8.88 (m, 1H), 8.21 (s, 1H), 7.97-7.95 (m, 1H), 7.87 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 4.76-4.40 (m, 2H), 4.10-3.96 (m, 2H), 3.88 (s, 3H), 3.76-3.69 (m, 4H), 3.26-3.20 (m, 4H). LCMS (M+H ⁺ ) m/z: 523.3.

Example 36:6 -(4- chlorophenyl )-N-(2- methoxy -6-(piperazin-1-yl)pyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (compound 36) manufacturing

[0320] Step 1: Synthesis of tert-butyl 4-(5-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate

[0321] To a solution of 6-bromo-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (300 mg, 0.91 mmol) in DMSO (10 mL) was added tert-butyl 4-(5-amino-6-methoxypyridin-2-yl)piperazine-1-carboxylate (280 mg, 0.91 mmol) was added. The reaction mixture was stirred at 120° C. for 1 hour under N ₂ . The mixture was added to water, extracted with EtOAc (80 mL x 3), washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated in vacuo, then purified by column chromatography on silica gel (DCM/CH ₃ OH = 60:1) to yield tert-butyl 4-(5-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyridonium Obtained midin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate (200 mg, 40% yield) as a yellow solid. LCMS (M+H ⁺ -Boc) m/z: 457.2

[0322] Step 2: Synthesis of tert-butyl 4-(5-((6-(4-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate

[0323] 디옥산/H ₂ O (10 mL, v/v = 5/1) 중 tert-부틸 4-(5-((6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)아미노)-6-메톡시피리딘-2-일)피페라진-1-카르복실레이트 (60 mg, 0.11 mmol), (4-클로로페닐)보론산 (50 mg, 0.33 mmol), Pd(dppf)Cl ₂ .DCM (18.0 mg, 0.02 mmol) 및 Na ₂ CO ₃ (35 mg, 0.33 mmol)의 혼합물을 실온에서 퍼징하고 N ₂ 로 3회 탈기한 다음 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated to remove the solvent and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to yield tert-butyl 4-(5-((6-(4-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazin-1-carboxy Silate (40 mg, 62% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 589.3.

[0324] Step 3: Synthesis of 6-(4-chlorophenyl)-N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

TFA (2 mL) was added. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and then purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to yield 6-(4-chlorophenyl)-N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (25 mg, 48% aqueous Yul, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.11 (br, 1H), 9.69 (s, 1H), 8.97-8.90 (m, 3H), 8.26 (s, 1H), 7.90 (br, 1H), 7.65 (dd, J = 6.8, 2.0 Hz, 2H), 7.58 (dd, J = 6.8, 2.0 Hz, 2H), 6.49 (d, J = 8.4 Hz, 1H), 4.51-4.46 (m, 2H), 4.02-3.98 (m, 2H), 3.86 (s, 3H), 3.72-3.47 (m, 4H), 3.25-3.23 (m, 4H). LCMS (M+H ⁺ ) m/z: 489.1.

Example 37: N-(2- methoxy -6- (piperazin-1-yl) pyridin-3-yl) -6-phenyl-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 37)

[0326] Step 1: Synthesis of tert-butyl 4-(6-methoxy-5-((6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate

[0327] Dioxane/H₂tert-butyl 4-(5-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol), (phenylboronic acid (27 mg, 0.22 mmol), Pd(dppf)Cl₂.DCM (18.0 mg, 0.02 mmol) and Na₂CO₃ (35 mg, 0.33 mmol) was purged at room temperature with N₂After degassing 3 times, the mixture was stirred at 100° C. for 16 hours. The reaction mixture was concentrated to remove the solvent and the residue was subjected to column chromatography on silica gel (DCM/CH₃OH = 30: 1) Purification gave tert-butyl 4-(6-methoxy-5-((6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate (38 mg, 62% yield) as a yellow solid. LCMS (M+H⁺) m/z: 555.4.

[0328] Step 2: Synthesis of N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0329] To a solution of tert-butyl 4-(6-methoxy-5-((6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate (45 mg, 0.08 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to give N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (30 mg, 67% yield, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.06 (br, 1H), 9.65 (s, 1H), 8.97-8.90 (m, 3H), 8.26 (s, 1H), 7.90 (br, 1H), 7.60-7.51 (m, 5H), 6.49 (d, J = 8.8 Hz, 1H), 4.63–4.46 (m, 2H), 4.03–3.99 (m, 2H), 3.86 (s, 3H), 3.51–3.45 (m, 4H), 3.25–3.23 (m, 4H). LCMS (M+H ⁺ ) m/z: 455.2.

Example 38: N-(2- methoxy -6-(piperazin-1-yl)pyridin-3-yl)-6-(p- Tolil )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 38)

[0330] Step 1: Synthesis of tert-butyl 4-(6-methoxy-5-((6-(p-tolyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate

[0331] tert- _Butyl 4-(5-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol), p-tolylboronic acid (50 mg, 0.32 mmol), Pd(dppf)Cl ₂ .DCM (18.0 mg, 0.02 mmol) and Na ₂ CO ₃ (35 mg, 0.33 mmol) was purged at room temperature, degassed with N ₂ 3 times and stirred at 100 °C for 16 hours. The reaction mixture was concentrated to remove the solvent and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to give tert-butyl 4-(6-methoxy-5-((6-(p-tolyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)piperazin-1-carboxy Silate (48 mg, 62% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 569.4.

Step 2: N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-6-(p-tolyl)-8,9-dihydroimidazo[1' Synthesis of 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine

TFA (2 mL) was added. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and then purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-6-(p-tolyl)-8,9-dihydroimidazo[1’,2’:1,6]pyrido[2,3-d]pyrimidin-2-amine (30 mg, 57% yield, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.05 (br, 1H), 9.63 (s, 1H), 9.08-8.98 (m, 3H), 8.22 (s, 1H), 7.91 (br, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 6.48 (d, J = 8.4 Hz, 1H), 4.48-4.46 (m, 2H), 4.03-3.99 (m, 2H), 3.86 (s, 3H), 3.73-3.70 (m, 4H), 3.25-3.23 (m, 4H), 2.40 (s, 3H). LCMS (M+H ⁺ ) m/z: 469.2.

Example 39: N-(2- methoxy -6-(piperazin-1-yl)pyridin-3-yl)-6-(pyridin-2-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[ 2,3-d] pyrimidin-2-amine (compound 39) manufacturing

[0334] Step 1: Synthesis of tert-butyl 4-(6-methoxy-5-((6-(pyridin-2-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate

[0335] tert-Butyl 4-(5-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate (45 mg, 0.08 mmol), 2-(tributylstannyl)pyridine in dioxane (10 mL) Dean (90 mg, 0.24 mmol), Pd(PPh ₃ ) ₂ Cl ₂ . (10.0 mg, 0.014 mmol) was purged at room temperature and degassed with N ₂ three times, then stirred at 100° C. for 16 hours. The reaction mixture was concentrated to remove the solvent and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to yield tert-butyl 4-(6-methoxy-5-((6-(pyridin-2-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)piperazin-1 -Carboxylate (20 mg, 42% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 556.2

[0336] Step 2: Synthesis of N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-6-(pyridin-2-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0337] TFA (2 mL) was added. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to give N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-6-(pyridin-2-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (2 mg, 7% yield) , TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.94-8.91 (m, 2H), 8.71-8.70 (m, 1H), 8.34 (br, 1H), 8.17-8.15 (m, 1H), 8.00-8.02 (m, 1H), 7.48-7.45 (m, 1H) ), 6.52–6.49 (m, 1H), 4.72–4.70 (m, 2H), 4.33–4.29 (m, 2H), 3.98 (s, 3H), 3.89–3.82 (m, 4H), 3.35–3.31 (m, 4H). LCMS (M+H ⁺ ) m/z: 456.2.

Example 40: N-(2- methoxy -6- (piperazin-1-yl) pyridin-3-yl) -6- (pyridin-3- ethynyl ) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (compound 40) manufacturing

[0338] Step 1: Synthesis of tert-butyl 4-(6-methoxy-5-((6-(pyridin-3-ylethynyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate

[0339] tert-butyl 4-(5-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol), 3-ethynylpyridine (13 mg) in DMF (10 mL) , 0.13 mmol), Pd(PPh ₃ ) ₂ Cl ₂ . (10.0 mg, 0.014 mmol), Et ₃ N (0.5 mL), CuI (5 mg, 0.03 mmol) was purged at room temperature, degassed 3 times with N ₂ and stirred at 60° C. for 16 hours. The reaction mixture was concentrated to remove the solvent and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to yield tert-butyl 4-(6-methoxy-5-((6-(pyridin-3-ylethynyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)piperazine Obtained -1-carboxylate (15 mg, 18% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 580.3.

[0340] Step 2: Synthesis of N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-6-(pyridin-3-ylethynyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0341] To a solution of tert-butyl 4-(6-methoxy-5-((6-(pyridin-3-ylethynyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate (15 mg, 0.04 mmol) in DCM (10 mL) FA (2 mL) was added. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to give N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-6-(pyridin-3-ylethynyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (5 mg, 7 % yield, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.90-8.83 (m, 2H), 8.63 (br, 1H), 8.42 (s, 1H), 8.29 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 6 .50-6.48 (m, 1H), 4.73-4.70 (m, 2H), 4.27-4.20 (m, 2H), 3.98 (s, 3H), 3.89-3.82 (m, 4H), 3.35-3.31 (m, 4H). LCMS (M+H ⁺ ) m/z: 480.1.

Example 41: N-(2- methoxy -6-(piperazin-1-yl)pyridin-3-yl)-6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (compound 41) manufacturing

[0342] Step 1: Synthesis of tert-butyl 4-(6-methoxy-5-((6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate

[0343] tert-butyl 4-(5-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol), 4-(tributylstannyl)pyridine in dioxane (10 mL) Dean (119 mg, 0.32 mmol), Pd(PPh ₃ ) ₂ Cl ₂ . (10.0 mg, 0.014 mmol) was purged at room temperature and degassed with N ₂ three times, then stirred at 100° C. for 16 hours. The reaction mixture was concentrated to remove the solvent and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to yield tert-butyl 4-(6-methoxy-5-((6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)piperazin-1- Carboxylate (20 mg, 42% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 556.2

[0344] Step 2: Synthesis of N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0345] TFA (2 mL) was added. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to give N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (2 mg, 7% yield) , TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.97-8.95 (m, 3H), 8.42 (s, 1H), 8.31 (d, J = 3.6 Hz, 1H), 7.94 (d, J = 5.2 Hz, 2H), 6.51 (d, J = 8.4 Hz, 1H), 4.74-4 .69 (m, 2H), 4.23-4.18 (m, 2H), 3.98 (s, 3H), 3.84-3.81 (m, 4H), 3.36-3.31 (m, 4H). LCMS (M+H ⁺ ) m/z: 456.1.

Example 42: Preparation of 1-(4-(2-((2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)amino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-methylpyrazin-2(1H)-one (Compound 42)

[0346] Step 1: Synthesis of tert-butyl 4-(6-methoxy-5-((6-(4-(3-methyl-2-oxopyrazin-1(2H)-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)piperazine-1-carboxylate

[0347] 디옥산/H ₂ O (10 mL, v/v = 5/1) 중 tert-부틸 4-(5-((6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)아미노)-6-메톡시피리딘-2-일)피페라진-1-카르복실레이트 (70 mg, 0.13 mmol), 3-메틸-1-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)피라진-2(1H)-온 (78 mg, 0.26 mmol), Pd(dppf)Cl ₂ .DCM (18.0 mg, 0.02 mmol) 및 Na ₂ CO ₃ (35 mg, 0.33 mmol)의 혼합물을 실온에서 퍼징하고 N ₂ 로 3회 탈기한 다음 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated to remove the solvent and the residue was purified by column chromatography on silica gel (DCM/CH ₃ OH = 30:1) to yield tert-butyl 4-(6-methoxy-5-((6-(4-(3-methyl-2-oxopyrazin-1(2H)-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl Obtained )amino)pyridin-2-yl)piperazine-1-carboxylate (38 mg, 52% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 663.4.

[0348] Step 2: Synthesis of 1-(4-(2-((2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-methylpyrazin-2(1H)-one

( 38 mg, 0.06 mmol) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and purified by prep-HPLC (0.1% TFA, CH ₃ CN in H ₂ O) to yield 1-(4-(2-((2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-methylpyrazine Obtained -2(1H)-one (18 mg, 57% yield, TFA salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.27 (br, 1H), 9.69 (s, 1H), 8.99-8.91 (m, 3H), 8.32 (s, 1H), 7.92-7.69 (m, 5H), 7.51 (d, J = 4.8 Hz, 1H), 7.29 (d, J = 4.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 4.51-4.45 (m, 2H), 4.10-4.04 (m, 2H), 4.06 (s, 3H), 3.72-3.3.70 (m, 4H), 3.29-3.25 (m, 4H), 2.38 (s, 3H). LCMS (M+H ⁺ ) m/z: 563.2.

Example 43:6 -Phenyl-N-(pyridin-4-yl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 43)

[0350] Step 1: Synthesis of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

A mixture of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5.0 g, 24.84 mmol) and NBS (4.86 g, 27.32 mmol) was dissolved in DMF (200 mL). The mixture was stirred at room temperature for 5 hours. The mixture was added to H ₂ O (300 mL) and filtered to give 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (3.0 g, 37 % yield) as a white solid.

[0352] Step 2: Synthesis of 6-bromo-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine

[0353] To a mixture of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2.5 g, 9.19 mmol) in CH ₃ CN (24 mL) was added POCl ₃ (6 mL). The mixture was stirred at 100 °C for 16 hours. The mixture was concentrated to give 6-bromo-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (3.0 g, crude crude) as a brown solid.

Step 3: Synthesis of 2-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol

A mixture of 6-bromo-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (3.0 g, 10.32 mmol) and 2-aminoethane-1-ol (3.15 g, 51.62 mmol) was dissolved in dioxane (30 mL). The mixture was stirred at 90 °C for 1 hour. The mixture was extracted with EtOAc (50 mL x 2). The organic phase was washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give 2-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (3.0 g, crude) as a yellow oil which was used directly in the next step.

[0356] Step 4: Synthesis of 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0357] To a mixture of 2-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (3.0 g, 9.52 mmol) and Et ₃ N (4.82 g, 47.59 mmol) in DCM (30 mL) was added MsCl (3.27 g, 28.55 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was added to H ₂ O (50 mL) and filtered to give 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (2.0 g, crude) as a yellow solid.

[0358] Step 5: Synthesis of 2-(methylthio)-6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0359] 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (300 mg, 1.01 mmol), phenylboronic acid (182 mg, 1.51 mmol), Pd(dppf)Cl ₂ (30 mg) and K ₂ CO ₃ (41 9 mg, 3.03 mmol) was stirred at 100°C for 2 hours. The mixture was concentrated in vacuo to give a crude which was purified by silica gel column flash chromatography (EtOAc/PE = 1:1, v/v) to give 2-(methylthio)-6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (80 mg, 30% yield) as a yellow solid.

[0360] Step 6: Synthesis of 2-(methylsulfinyl)-6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0361] A solution of 2-(methylthio)-6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (80 mg, 0.27 mmol) and m-CPBA (70 mg, 0.4 mmol) in DCM (10 mL) was stirred at room temperature for 1 hour. The reaction was concentrated to give 2-(methylsulfinyl)-6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (130 mg crude) which was used directly in the next step.

[0362] Step 7: Synthesis of 6-phenyl-N-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0363] A mixture of 2-(methylsulfinyl)-6-phenyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (130 mg, 0.43 mmol) and pyridin-4-amine (40 mg, 0.43 mmol) in DMSO (3 mL) was stirred at 120°C for 1 hour. The mixture was purified twice by preparative-HPLC (0.1% NH ₄ HCO _{3 ,} CH ₃ CN in water) to give 6-phenyl-N-(pyridin-4-yl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (26.6 mg, 36% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 9.24 (d, J = 8.0 Hz, 2H), 8.57 (s, 1H), 7.65–7.62 (m, 2H), 7.48 (s, 1H), 7.41–7.31 (m, 3H), 6.91 (d, J = 8.0 Hz, 2H), 4.27–4.22 (m, 2H) ), 4.11–4.06 (m, 2H). LCMS (M+H ⁺ ) m/z: 341.0.

Example 44:6 -(pyridin-2-yl)-N-(pyridin-4-yl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 44)

[0364] Step 1: Synthesis of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0365] A solution of 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (400 mg, 1.35 mmol) and m-CPBA (465 mg, 2.69 mmol) in DCM (30 mL) was stirred at room temperature for 10 minutes. The reaction was concentrated to give 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg crude) which was used directly in the next step.

[0366] Step 2: Synthesis of 6-bromo-N-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0367] A mixture of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (600 mg, 1.92 mmol) and pyridin-4-amine (180 mg, 1.92 mmol) in DMSO (6 mL) was stirred at 120°C for 1 hour. The mixture was purified by preparative-HPLC (0.1% formic acid, MeCN in water) to afford 6-bromo-N-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (100 mg, 15% yield) as a yellow solid.

[0368] Step 3: Synthesis of 6-(pyridin-2-yl)-N-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0369] 6-Bromo-N-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (45 mg, 0.13 mmol), 2-(tributylstannyl)pyridine (97 mg, 0.26 mmol), Pd(PPh ₃ ) ₄ (10 mg) in dioxane (3 mL) and XantPhos (10 mg) was stirred at 120°C for 16 hours. The mixture was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to afford 6-(pyridin-2-yl)-N-(pyridin-4-yl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (9.9 mg, 22% yield, formic acid salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.32 (s, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.65-8.64 (m, 2H), 8.44-8.34 (m, 3H), 8.22 (s, 2H), 7.87-7.82 (m, 3H), 7.37-7.34 (m, 1H), 4.17-4.14 (m, 4H). LCMS (M+H ⁺ ) m/z: 342.2.

Example 45: N,6 Preparation of -di(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (Compound 45)

[0370] Step 1: Synthesis of 2-(methylthio)-6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0371] 6-Bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (300 mg, 1.01 mmol), pyridin-4-ylboronic acid (185 mg, 1.51 mmol), Pd(dppf)Cl ₂ (30 mg) and K ₂ CO in dioxane (30 mL) A solution of ₃ (419 mg, 3.03 mmol) was stirred at 100 °C for 2 h. The mixture was concentrated in vacuo to give a crude which was purified by silica gel column flash chromatography (EtOAc/PE = 1:1, v/v) to give 2-(methylthio)-6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 40% yield) as a yellow solid.

[0372] Step 2: Synthesis of 2-(methylsulfinyl)-6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0373] A solution of 2-(methylthio)-6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (40 mg, 0.14 mmol) and m-CPBA (71 mg, 0.41 mmol) in DCM (10 mL) was stirred at room temperature for 10 minutes. The reaction was concentrated to give 2-(methylsulfinyl)-6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (80 mg crude) which was used directly in the next step.

[0374] Step 3: Synthesis of N,6-di(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0375] A mixture of 2-(methylsulfinyl)-6-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (80 mg, 0.26 mmol) and pyridin-4-amine (24 mg, 0.26 mmol) in DMSO (3 mL) was stirred at 120°C for 1 hour. The mixture was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to give N,6-di(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (12.2 mg, 14% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.68–8.60 (m, 3H), 8.43 (d, J = 8.0 Hz, 2H), 7.95–7.90 (m, 3H), 6.31 (d, J = 8.0 Hz, 2H), 4.20–4.03 (m, 4H). LCMS (M+H ⁺ ) m/z: 342.1.

Example 46:6 -(3- Chloropyridine -4-yl)-N-(pyridin-4-yl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 46)

[0376] Step 1: Synthesis of 6-(3-chloropyridin-4-yl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0377] 6-Bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (150 mg, 0.5 mmol), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (181 mg, 0.76 mmol), Pd(dppf)Cl ₂ (30 mg) and K ₂ CO ₃ (209 mg, 1.51 mmol) were stirred at 100° C. for 6 h. The mixture was concentrated in vacuo to give a crude which was purified by silica gel column flash chromatography (DCM/MeOH = 20:1, v/v) to give 6-(3-chloropyridin-4-yl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (80 mg, 48% yield) as a yellow solid.

[0378] Step 2: Synthesis of 6-(3-chloropyridin-4-yl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0379] A solution of 6-(3-chloropyridin-4-yl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (70 mg, 0.21 mmol) and m-CPBA (55 mg, 0.32 mmol) in DCM (10 mL) was stirred at room temperature for 10 minutes. The reaction was concentrated to give 6-(3-chloropyridin-4-yl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (120 mg crude) which was used directly in the next step.

[0380] Step 3: Synthesis of 6-(3-chloropyridin-4-yl)-N-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0381] A mixture of 6-(3-chloropyridin-4-yl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (120 mg, 0.35 mmol) and pyridin-4-amine (33 mg, 0.35 mmol) in DMSO (3 mL) was stirred at 70°C for 1 hour. The reaction was monitored by LCMS and found to be effective. The mixture was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to afford 6-(3-chloropyridin-4-yl)-N-(pyridin-4-yl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (33.8 mg, 26% yield, formic acid salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.58 (br, 1H), 9.19 (d, J = 7.2 Hz, 2H), 8.78–8.74 (m, 2H), 8.62 (d, J = 4.8 Hz, 1H), 8.50 (s, 1H), 7.66 (s, 1H), 7.56 (d, J = 4.8 Hz, 1H), 7.08 (d, J = 7.2 Hz, 2H), 4.21 (t, J = 9.6 Hz, 2H), and 4.06 (t, J = 9.6 Hz, 2H). LCMS (M+H ⁺ ) m/z: 376.2.

Example 47:6 -(2,4- dichlorophenyl )-N-(pyridin-4-yl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 47)

[0382] Step 1: Synthesis of 6-(2,4-dichlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0383] 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (300 mg, 1.01 mmol), (2,4-dichlorophenyl)boronic acid (288 mg, 1.51 mmol), Pd(dppf)Cl ₂ (30 mg) and K ₂ in dioxane (30 mL) A solution of CO ₃ (419 mg, 3.03 mmol) was stirred at 100° C. for 2 h. The mixture was concentrated in vacuo to give crude which was purified by silica gel column flash chromatography (EtOAc/PE = 1:1, v/v) to give 6-(2,4-dichlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (80 mg, 30% yield) as a yellow solid.

[0384] Step 2: Synthesis of 6-(2,4-dichlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0385] A solution of 6-(2,4-dichlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (70 mg, 0.19 mmol) and m-CPBA (50 mg, 0.29 mmol) in DCM (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give 6-(2,4-dichlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg crude) which was used directly in the next step.

[0386] Step 3: Synthesis of 6-(2,4-dichlorophenyl)-N-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0387] A mixture of 6-(2,4-dichlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 0.26 mmol) and pyridin-4-amine (25 mg, 0.26 mmol) in DMSO (3 mL) was stirred at 120°C for 1 hour. The mixture was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to afford 6-(2,4-dichlorophenyl)-N-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (38.5 mg, 36 % yield, formic acid salt) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 9.25 (d, J = 8.0 Hz, 2H), 8.59 (s, 1H), 8.45 (s, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 7.35 (d, J = 1.6 Hz, 2H), 6.92 (dd, J = 6.0, 1.6 Hz, 2H), 4.27 (t, J = 9.6 Hz, 2H), 4.04 (t, J = 9.6 Hz, 2H). LCMS (M+H ⁺ ) m/z: 409.0.

Example 48:6 -(2,6- dichlorophenyl )-N-(2-(4- Methylpiperazine -1-yl)ethyl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 48)

[0388] Step 1: Synthesis of 6-(2,6-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0389] To a solution of methyl 2-(2,6-dichlorophenyl)acetate (4.38 g, 20 mmol) in THF (60 mL) was added LiHMDS (40 mL, 40 mmol) dropwise at -78 °C. The mixture was stirred at -78 °C for 3 hours. Then 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (3.38 g, 20 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was added to NH ₄ Cl aq (30 mL). The mixture was extracted with EtOAc (50 mL x 2) and the combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain the crude product on silica gel column flash chromatography (EtOAc/PE = 1/1, v/v) to obtain 6-(2,6-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8 H)-one (2.2 g, 32 % yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 337.9.

[0390] Step 2: Synthesis of 7-chloro-6-(2,6-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine

[0391] To a solution of 6-(2,6-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2.2 g, 6.4 mmol) in CH ₃ CN (25 mL) was added POCl ₃ (10 mL). The mixture was stirred at 100° C. for 16 hours. The mixture was concentrated to give crude material. The crude was extracted with EtOAc (20 mL x 2) and the combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product which was purified by silica gel column flash chromatography (EtOAc/PE = 1/4, v/v) to obtain 7-chloro-6-(2,6-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrido Midine (1.5 g, 65 % yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 355.8.

[0392] Step 3: Synthesis of 2-((6-(2,6-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol

[0393] To a solution of 7-chloro-6-(2,6-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine (712 mg, 2 mmol) in 1,4-dioxane (10 mL) was added 2-aminoethane-1-ol (366 mg, 6 mmol). The mixture was stirred at 90° C. for 16 hours. The mixture was extracted with EtOAc (10 mL x 2) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product which was purified by silica gel column flash chromatography (DCM/MeOH=10/1, v/v) to give 2-((6-(2,6-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine-7 Obtained -yl)amino)ethane-1-ol (705 mg, 92 % yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 381.0.

[0394] Step 4: Synthesis of 6-(2,6-dichlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0395] To a solution of 2-((6-(2,6-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (705 mg, 1.85 mmol) in DCM (30 mL) was added Et ₃ N (2.6 g, 25.9 mmol) and MsCl (1.47 g, 12.9 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was extracted with DCM (10 mL x 2) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product which was purified by silica gel column flash chromatography (DCM/MeOH = 20/1, v/v) to obtain 6-(2,6-dichlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2' :1,6]pyrido[2,3-d]pyrimidine (640 mg, 95% yield) as a yellow oil. LCMS (M+H ⁺ ) m/z: 363.0.

[0396] Step 5: Synthesis of 6-(2,6-dichlorophenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0397] To a solution of 6-(2,6-dichlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (50 mg, 0.14 mmol) in DMSO (3 mL) was added 2-(4-methylpiperazin-1-yl)ethan-1-amine (40 mg, 0.28 mmol). The mixture was stirred at 120° C. for 16 hours. The mixture was extracted with EtOAc (10 mL x 2) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product which was purified by pre-HPLC (10 mM NH ₄ HCO ₃ ) to give 6-(2,6-dichlorophenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-8,9-di Hydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (5.6 mg, 9 % yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.27 (s, 1H), 7.51-7.48 (m, 2H), 7.41-7.36 (m, 1H), 7.24 (s, 1H), 4.31-4.22 (m, 2H), 4.05-3.99 (m, 2H), 3. 71-3.62 (m, 2H), 2.70-2.53 (m, 10H), 2.32 (s, 3H). LCMS (M+H ⁺ ) m/z: 458.0.

Example 49:6 -(2,6- dichlorophenyl )-N-(2-(piperidin-4-yl)ethyl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-amine (Compound 49)

[0398] Step 1: Synthesis of 6-(2,6-dichlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0399] To a solution of 6-(2,6-dichlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (200 mg, 0.82 mmol) in CH ₃ CN (3 mL) and H ₂ O (3 mL) was added Oxone (509 mg, 0.83 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture is used directly in the next reaction. LCMS (M+H ⁺ ) m/z: 394.9.

[0400] Step 2: Synthesis of tert-butyl 4-(2-((6-(2,6-dichlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate

[0401] To a solution of 6-(2,6-dichlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (200 mg, 0.5 mmol) in CH ₃ CN (3 mL) and H ₂ O (3 mL) was added tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate ( 342 mg, 1.5 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was extracted with EtOAc (10 mL x 2) and the combined organic layers were washed with brine (10 mL), purified over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo to give the crude product which was purified by silica gel column flash chromatography (DCM/MeOH = 10/1 , v/v) to yield tert-butyl 4-(2-((6-(2,6-dichlorophenyl)-8,9-dihydroimine Obtained polyzo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate (68 mg, 25% yield) as a yellow oil. LCMS (M+H ⁺ ) m/z: 543.3.

[0402] Step 3: Synthesis of 6-(2,6-dichlorophenyl)-N-(2-(piperidin-4-yl)ethyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0403] To a solution of tert-butyl 4-(2-((6-(2,6-dichlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)ethyl)piperidine-1-carboxylate (68 mg, 0.13 mmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give crude material. This crude material was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to afford 6-(2,6-dichlorophenyl)-N-(2-(piperidin-4-yl)ethyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (11.5 mg, 20% yield, formic acid salt) as yellow Obtained as an oil. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.77-8.73 (m, 1H), 8.49 (s, 2H), 7.98-7.93 (m, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.52 (t, J = 8.0 Hz, 1H), 4.73-7.67 (m, 2H), 4.18-4.13 (m, 2H), 3.63 (t, J = 7.2 Hz, 2H), 3.44-3.40 (m, 2H), 3.03-2.97 (m, 2H), 2.09-2.05 (m, 2H), 1.75-1.69 (m, 3H), 1.50-1.45 (m, 2H). LCMS (M+H ⁺ ) m/z: 443.0.

Example 50:6 -(2,6- dichlorophenyl )-2-(piperazine-1-yl)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidine (Compound 50)

[0404] Step 1: Synthesis of 6-(2,6-dichlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0405] To a solution of 6-(2,6-dichlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (150 mg, 0.41 mmol) in CH ₃ CN (3 mL) and H ₂ O (3 mL) was added Oxone (386 mg, 0.63 mmol). The mixture was stirred at room temperature for 16 hours. This reaction mixture is used directly in the next reaction. LCMS (M+H ⁺ ) m/z: 394.9.

[0406] Step 2: Synthesis of tert-butyl 4-(6-(2,6-dichlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)piperazine-1-carboxylate

[0407] To a mixture of 6-(2,6-dichlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (150 mg, 0.38 mmol) in CH ₃ CN (3 mL) and H ₂ O (3 mL) was added tert-butyl piperazine-1-carboxylate (212 mg, 1. 14 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was extracted with EtOAc (10 mL x 2) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product which was purified by silica gel column flash chromatography (DCM/MeOH = 10/1 , v/v) to give tert-butyl 4-(6-(2,6-dichlorophenyl)-8,9-dihydroimidazo [1', Obtained 2':1,6]pyrido[2,3-d]pyrimidin-2-yl)piperazine-1-carboxylate (60 mg, 31 % yield) as a yellow oil. LCMS (M+H ⁺ ) m/z: 501.0.

[0408] Step 3: Synthesis of 6-(2,6-dichlorophenyl)-2-(piperazin-1-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0409] To a solution of tert-butyl 4-(6-(2,6-dichlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give crude material. The crude material was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to afford 6-(2,6-dichlorophenyl)-2-(piperazin-1-yl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine (9.4 mg, 17% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.85 (s, 1H), 8.02 (s, 1H), 7.58-7.55 (m, 2H), 7.50-7.45 (m, 1H), 4.70-4.65 (m, 2H), 4.25-4.22 (m, 4H), 4. 15-4.11 (m, 2H), 3.30-3.25 (m, 4H). LCMS (M+H ⁺ ) m/z: 401.0.

Example 51:6 -(2,6- dichlorophenyl Preparation of )-2-(4-(pyridin-4-yl)piperazin-1-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (Compound 51)

[0410] Step 1: 6-(2,6-dichlorophenyl)-2-(4-(pyridin-4-yl)piperazin-1-yl)-8,9-dihydroimidazo[1',2 Synthesis of ':1,6]pyrido[2,3-d]pyrimidine

[ ₀₄₁₁ ] 1-( _pyridin -4-yl)piperazine (371 mg, 2.2 8 mmol) was added. The mixture was stirred at room temperature for 16 hours. The crude material was purified by preparative-HPLC (10 mM NH ₄ HCO ₃ ) to afford 6-(2,6-dichlorophenyl)-2-(4-(pyridin-4-yl)piperazin-1-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (19.0 mg, 5% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.16 (d, J = 7.6 Hz, 2H), 8.74 (s, 1H), 7.62-7.56 (m, 3H), 7.52-7.47 (m, 1H), 7.40 (d, J = 8.0 Hz, 2H), 4.26-4. 23 (m, 2H), 4.06–4.03 (m, 2H), 3.81–3.72 (m, 4H), 3.31–3.28 (m, 2H), 2.91–2.82 (m, 2H). LCMS (M+H ⁺ ) m/z: 478.0.

Example 52:6 -(2,6- dichlorophenyl )-N-(pyridin-4-yl)-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-amine (compound 52) manufacturing

[0412] Step 1: Synthesis of 6-(2,6-dichlorophenyl)-N-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0413] To a solution of 6-(2,6-dichlorophenyl)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (300 mg, 0.76 mmol) in CH ₃ CN (3 mL) and H ₂ O (3 mL) was added pyridin-4-amine (214 mg, 2.28 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated to give crude material. This crude material was purified by preparative-HPLC (10 mM NH ₄ HCO ₃ ) to afford 6-(2,6-dichlorophenyl)-N-(pyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (10.2 mg, 3% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.01-9.96 (m, 3H), 8.69 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.51 (s, 1H), 7.50-7.47 (m, 1H), 6.86-6.84 (m, 2H) ), 4.22 (t, J = 9.2 Hz, 2H), 4.02 (t, J = 9.2 Hz, 2H). LCMS (M+H ⁺ ) m/z: 409.0.

Example 53:6 -Phenyl-N-(pyridin-4-yl)-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -2-amine (compound 53) manufacturing

[0414] Step 1: Synthesis of 3-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)propan-1-ol

A mixture of 6-bromo-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (6.5 g, 22.37 mmol) and 3-aminopropan-1-ol (8.4 g, 111.85 mmol) was dissolved in dioxane (30 ml). The mixture was stirred at 90 °C for 1 hour. The mixture was extracted with EtOAc (50 mL x 2). The organic phase was washed with brine (50 mL), Na ₂ SO ₄ dried and concentrated in vacuo to give a crude which was purified by silica gel column flash chromatography (EtOAc/PE = 3:1, v/v) to give 3-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)propan-1-ol (5.0 g, 68% yield) as a yellow solid.

[0416] Step 2: Synthesis of 6-bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

A mixture of 3-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)propan-1-ol (2.0 g, 6.07 mmol) and Et ₃ N (3 mL) was dissolved in DCM (30 mL) then MsCl (1 mL) was added. The mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo to give the crude which was purified by silica gel column flash chromatography (EtOAc/PE = 3:1, v/v) to give 6-bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (1.2 g, 63% yield) as a yellow solid.

[0418] Step 3: Synthesis of 2-(methylthio)-6-phenyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0419] 6-bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (200 mg, 0.64 mmol), phenylboronic acid (117 mg, 0.96 mmol), Pd(dppf)Cl ₂ (30 mg) and K ₂ CO ₃ (266 mg, 1.92 mmol) was stirred at 100 °C for 2 h. The mixture was concentrated in vacuo to give a crude which was purified by silica gel column flash chromatography (MeOH/DCM = 10:1, v/v) to give 2-(methylthio)-6-phenyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidine (150 mg, 70% yield) as a yellow solid.

[0420] Step 4: Synthesis of 2-(methylsulfinyl)-6-phenyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0421] A solution of 2-(methylthio)-6-phenyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (50 mg, 0.16 mmol) and m-CPBA (112 mg, 0.62 mmol) in DCM (15 mL) was stirred at room temperature for 10 minutes. The reaction was concentrated to give 2-(methylsulfinyl)-6-phenyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (150 mg, crude) which was used directly in the next step.

[0422] Step 5: Synthesis of 6-phenyl-N-(pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0423] A mixture of 2-(methylsulfinyl)-6-phenyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (150 mg, 0.46 mmol) and pyridin-4-amine (44 mg, 0.46 mmol) in DMSO (3 mL) was stirred at 70°C for 1 hour. The mixture was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ ) (0.1% formic acid, CH ₃ CN in water) to afford 6-phenyl-N-(pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-amine (5.4 mg, 0.03 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.84-8.82 (m, 2H), 8.66 (s, 1H), 7.52 (d, J = 6.4 Hz, 2H), 7.43-7.31 (m, 5H), 6.66-6.61 (s, 1H), 4.23 (s, 2H), 3.54 (s, 2H), 1.92 ( s, 2H). LCMS (M+H ⁺ ) m/z: 354.6.

Example 54:6 -(2- chlorophenyl )-N-(pyridin-4-yl)-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -2-amine (compound 54) manufacturing

[0424] Step 1: Synthesis of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0425] To a mixture of 6-bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (200 mg, 0.64 mmol) in DCM (5 mL) was added m-CPBA (332 mg, 1.93 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove DCM to give crude 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (241 mg) which was used directly in the next step. LCMS (M+H ⁺ ) m/z: 326.8.

[0426] Step 2: Synthesis of 6-bromo-N-(pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0427] To a solution of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (241 mg, 0.74 mmol) in DMSO (4 mL) was added pyridin-4-amine (83 mg, 0.88 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to afford 6-bromo-N-(pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-amine (60 mg, 23% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 356.5.

[0428] Step 3: Synthesis of 6-(2-chlorophenyl)-N-(pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0429] (2-chlorophenyl)boronic acid (12 mg, 0.072 mmol), Pd(dppf)Cl ₂ (2 mg, 0.0 03 mmol), K ₂ CO ₃ (26 mg, 0.18 mmol) and H ₂ O (0.2 mL) were added. The mixture was stirred at 60° C. for 2 hours. The mixture was concentrated to give the crude product which was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to give 6-(2-chlorophenyl)-N-(pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (6.2 mg, 29% yield, formic acid salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.27 (d, J = 7.6 Hz, 2H), 9.22 (s, 1H), 8.74 (s, 1H), 8.39 (s, 2H), 7.51-7.48 (m, 1H), 7.42-7.33 (m, 4H), 7. 05 (d, J = 8.0 Hz, 2H), 4.27–4.24 (m, 2H), 3.49–3.46 (m, 2H), 1.92–1.89 (m, 2H). LCMS (M+H ⁺ ) m/z: 389.0.

Example 55: N-(3- Fluoropyridine -4-yl) -6-phenyl-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -2-amine (compound 55) manufacturing

[0430] Step 1: Synthesis of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0431] A solution of 6-bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (150 mg, 0.48 mmol) and m-CPBA (169 mg, 0.96 mmol) in DCM (80 mL) was stirred at room temperature for 10 minutes. The reaction was concentrated to give 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (400 mg, crude) which was used directly in the next step.

[0432] Step 2: Synthesis of 6-bromo-N-(3-fluoropyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0433] A mixture of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (400 mg, 1.22 mmol) and 3-fluoropyridin-4-amine (137 mg, 1.22 mmol) in DMSO (5 mL) was stirred at 70°C for 5 hours. The mixture was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ ) to afford 6-bromo-N-(3-fluoropyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-amine (41 mg, 23% yield in 2 steps) as a yellow solid.

[0434] Step 3: Synthesis of N-(3-fluoropyridin-4-yl)-6-phenyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0435] 6-Bromo-N-(3-fluoropyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (36 mg, 0.09 mmol), phenylboronic acid (17 mg, 0.14 mmol), Pd(dppf)Cl ₂ (5 mg) and K ₂ CO in dioxane (20 mL) A solution of ₃ (39 mg, 0.28 mmol) was stirred at 70 °C for 2 h. The mixture was purified twice by preparative-HPLC (0.1% NH ₄ HCO ₃ ) to give N-(3-fluoropyridin-4-yl)-6-phenyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (6.4 mg, 18 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.63 (d, J = 8.4 Hz, 1H), 8.59 (s, 1H), 8.46 (dd, J = 8.0, 1.2 Hz, 1H), 7.53–7.50 (m, 2H), 7.42–7.29 (m, 5H), 6.45 (t, J = 8.4 Hz, 1H), 4. 22 (t, J = 5.6 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), and 1.95–1.89 (m, 2H). LCMS (M+H ⁺ ) m/z: 373.1.

Example 56: N-(2- fluorophenyls )-6-phenyl-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -2-amine (compound 56) manufacturing

[0436] Step 1: Synthesis of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0437] A solution of 6-bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (300 mg, 0.96 mmol) and m-CPBA (333 mg, 1.93 mmol) in DCM (100 mL) was stirred at room temperature for 10 minutes. The reaction was concentrated to give 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (500 mg, crude) which was used directly in the next step.

[0438] Step 2: Synthesis of 6-bromo-N-(2-fluorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0439] A mixture of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (500 mg, 1.53 mmol) and 2-fluoroaniline (849 mg, 7.64 mmol) in DMSO (5 mL) was stirred at 70°C for 8 hours. The mixture was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to afford 6-bromo-N-(2-fluorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-amine (80 mg, 22% yield in 2 steps) as a yellow solid.

[0440] Step 3: Synthesis of N-(2-fluorophenyl)-6-phenyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0441] 6-Bromo-N-(2-fluorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (30 mg, 0.08 mmol), phenylboronic acid (15 mg, 0.12 mmol), Pd(dppf)Cl ₂ (5 mg) and K ₂ CO ₃ (33 mg) in dioxane (2 mL) , 0.24 mmol) was stirred at 70 °C for 2 h. The mixture was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) and (0.1% NH ₄ HCO ₃ ) to afford N-(2-fluorophenyl)-6-phenyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-amine (8.4 mg, 28% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.22 (s, 1H), 8.35 (s, 1H), 7.84–7.80 (m, 1H), 7.48 (dd, J = 8.0, 1.6 Hz, 2H), 7.36–7.13 (m, 7H), 4.04 (t, J = 5.6 Hz, 2H), 3.45 (t, J = 5.6 Hz, 2H), 1.88–1.82 (m, 2H). LCMS (M+H ⁺ ) m/z: 372.1.

Example 57: N-(2- fluorophenyls )-6-(1H-indol-4-yl)-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -2-amine (compound 57) manufacturing

[0442] Step 1: Synthesis of N-(2-fluorophenyl)-6-(1H-indol-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0443] 6-Bromo-N-(2-fluorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (30 mg, 0.08 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (29 mg) in dioxane (2 mL) , 0.12 mmol), Pd(dppf)Cl ₂ (5 mg) and K ₂ CO ₃ (33 mg, 0.24 mmol) was stirred at 70° C. for 2 h. The mixture was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to afford N-(2-fluorophenyl)-6-(1H-indol-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-amine (13 mg, 28% yield, formic acid salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.16 (s, 1H), 9.46 (s, 1H), 8.53 (s, 1H), 8.29 (s, 1H), 7.83 (t, J = 5.6 Hz, 1H), 7.45-7.37 (m, 2H), 7.34-7.32 (m, 1H), 7.31-7.23 (m, 1H), 7.23-7.15 (m, 2H), 7.14-7.08 (m, 1H), 7.02 (dd, J = 7.2, 0.8 Hz, 1H), 6.32-6.30 (m, 1H), 4.16 (t, J = 5.6 Hz, 2H), 3.37 (t, J = 5.6 Hz, 2H), 1.95–1.93 (m, 2H). LCMS (M+H ⁺ ) m/z: 411.1.

Example 58: N-(2- fluorophenyls )-6-(1H- indazole -4-day)-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -2-amine (compound 58) manufacturing

[0444] Step 1: Synthesis of N-(2-fluorophenyl)-6-(1H-indazol-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0445] 6-Bromo-N-(2-fluorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (20 mg, 0.05 mmol) in dioxane (2 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (20 mg, 0.08 mmol), Pd(dppf)Cl ₂ (5 mg) and K ₂ CO ₃ (22 mg, 0.16 mmol) was stirred at 70° C. for 2 h. The mixture was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to afford N-(2-fluorophenyl)-6-(1H-indazol-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (4.1 mg, 19% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.77 (s, 1H), 8.45 (s, 1H), 7.94 (s, 1H), 7.89–7.87 (m, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.19–7.12 (m, 5H), 4. 47 (t, J = 5.2 Hz, 2H), 3.40 (t, J = 5.2 Hz, 2H), and 2.16–2.13 (m, 2H). LCMS (M+H ⁺ ) m/z: 412.0.

Example 59: N-(2- fluorophenyls )-6-(5- methyl -1H- indazole -4-day)-9,10- dihydro -8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (compound 59) manufacturing

[0446] Step 1: Synthesis of N-(2-fluorophenyl)-6-(5-methyl-1H-indazol-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0447] 6-Bromo-N-(2-fluorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (40 mg, 0.11 mmol) in dioxane (20 mL), 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-yne A solution of dazole (40 mg, 0.16 mmol), Pd(dppf)Cl ₂ (5 mg) and K ₂ CO ₃ (44 mg, 0.32 mmol) was stirred at 70° C. for 2 h. The mixture was purified twice by preparative-HPLC (0.1% NH ₄ HCO ₃ ) to afford N-(2-fluorophenyl)-6-(5-methyl-1H-indazol-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-amine (7.7 mg, 17% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.94 (s, 1H), 8.56 (s, 1H), 8.01–7.98 (m, 2H), 7.86 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.31–7.24 (m, 4H), 4. 64-4.60 (m, 2H), 3.55-3.45 (m, 2H), 2.36 (s, 3H), 2.31-2.24 (s, 2H). LCMS (M+H ⁺ ) m/z: 426.1.

Example 60:6 -(2- chlorophenyl )-N-(3- methoxyphenyl )-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -2-amine (compound 60) manufacturing

[0448] Step 1: Synthesis of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0449] To a mixture of 6-bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (100 mg, 0.3 mmol) in DCM (4 mL) was added m-CPBA (165 mg, 0.9 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove DCM to give crude 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (242 mg) which was used directly in the next step. LCMS (M+H ⁺ ) m/z: 327.0.

[0450] Step 2: Synthesis of 6-bromo-N-(3-methoxyphenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0451] A mixture of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (242 mg, crude, 0.3 mmol) and 3-methoxybenzenamine (184 mg, 1.5 mmol) in DMSO (4 mL) was stirred at 70 °C for 2 h and then detected by LCMS. Indicated 40% completion. The reaction mixture was purified by HPLC to give 6-bromo-N-(3-methoxyphenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (26 mg, 22% yield in 2 steps). LCMS (M+H ⁺ ) m/z: 386.0.

[0452] Step 3: Synthesis of 6-(2-chlorophenyl)-N-(3-methoxyphenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0453] 6-Bromo-N-(3-methoxyphenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (24 mg, 0.06 mmol), 2-chlorophenylboronic acid (12 mg, 0.08 mmol), K ₂ CO ₃ (25 mg, 0.18 mmol), and Pd(dppf)Cl A mixture of ₂ (5 mg, 0.006 mmol, 10 mol %) was suspended in THF (3 mL) and H ₂ O (0.5 mL) under N ₂ , protection and the reaction mixture was refluxed for 3-5 hours. The reaction solution was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to give 6-(2-chlorophenyl)-N-(3-methoxyphenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-amine (3.6 mg, formic acid salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.81 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 7.59 (t, J = 2.0 Hz, 1H), 7.48-7.45 (m, 1H), 7.36-7.28 (m, 4H), 7.20 (t, J = 8.0 Hz, 1H), 7.14 (s, 1H), 6.57 (dd, J = 8.0, 2.0, 1H), 4.18-4.16 (m, 2H), 3.76 (s, 3H), 3.38-3.37 (m, 2H), 1.90-1.86 (m, 2H). LCMS (M+H ⁺ ) m/z: 418.1.

Example 61:6 -(2- chlorophenyl )-N-(2- methoxyphenyl )-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -2-amine (compound 61) manufacturing

[0454] Step 1: Synthesis of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0455] 6-Bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine in DCM (5 mL) ( 200 mg, 0.64 mmol) was added m-CPBA (332 mg, 1.93 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove DCM to give crude 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dpi Rimidine (230 mg) was obtained and used directly in the next step. LCMS (M+H ⁺ ) m/z: 327.0.

[0456] Step 2: Synthesis of 6-bromo-N-(2-methoxyphenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0457] 6-Bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine in DMSO (4 mL) (230 mg, 0.7 mmol) was added 2-methoxyaniline (129 mg, 1.05 mmol). The mixture was stirred at 120° C. for 2 hours. The mixture was extracted with EtOAc (10 mL x 2) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product which was analyzed by silica gel column flash chromatography ( DCM/MeOH = 1/1, v/v) to obtain 6-bromo-N-(2-methoxyphenyl)-9,10-dihydro-8H-pyrido[1,6-a:2, Obtained 3-d']dipyrimidin-2-amine (43 mg, 15.9 % yield) as a yellow oil. LCMS (M+H ⁺ ) m/z: 385.9.

[0458] Step 3: Synthesis of 6-(2-chlorophenyl)-N-(2-methoxyphenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0459] To a solution of 6-bromo-N-(2-methoxyphenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (20 mg, 0.05 mmol) in THF (2 mL) was added (2-chlorophenyl)boronic acid (10 mg, 0.06 mmol), Pd(dppf)Cl ₂ (2 mg, 0.00 2 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol) and H ₂ O (0.2 mL) were added. The mixture was stirred at 60° C. for 2 hours. The mixture was extracted with EtOAc (10 mL x 2) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product which was purified by preparative-HPLC (0.1 % formic acid, CH ₃ CN in water) to give 6-(2-chlorophenyl)-N-(2-methoxyphenyl)-9,10-dihydro-8H-pyrido[ Obtained 1,6-a:2,3-d']dipyrimidin-2-amine (4.2 mg, 20% yield, formic acid salt) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.42 (s, 1H), 8.35 (s, 1H), 8.23 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.49-7.46 (m, 1H), 7.38-7.35 (m, 2H), 7.34-7.30 (m, 1H), 7.19 (s, 1H), 7.08-7.06 (m, 2H), 7.01-6.97 (m, 1H), 4.13-4.10 (m, 2H), 3.87 (s, 3H), 2.46-2.44 (m, 2H), 1.89-1.86 (m, 2H). LCMS (M+H ⁺ ) m/z: 418.0.

Example 62: N-(2- methoxyphenyl )-6-(5- methyl -1H- indazole -4-day)-9,10- dihydro -8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (compound 62) manufacturing

[0460] Step 1: Synthesis of N-(2-methoxyphenyl)-6-(5-methyl-1H-indazol-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0461] To a solution of 6-bromo-N-(2-methoxyphenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (23 mg, 0.06 mmol) in THF (2 mL) was added 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Indazole (18 mg, 0.07 mmol), Pd(dppf)Cl ₂ (3 mg, 0.003 mmol), K ₂ CO ₃ (25 mg, 0.18 mmol) and H ₂ O (0.2 mL) were added. The mixture was stirred at 60° C. for 16 hours. The mixture was extracted with EtOAc (10 mL x 2) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product which was purified by preparative-HPLC (0.1 % formic acid, CH ₃ CN in water) to obtain N-(2-methoxyphenyl)-6-(5-methyl-1H-indazol-4-yl)-9,10-dihydride Obtained rho-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (5.1 mg, 20% yield, formic acid salt) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.82 (s, 1H), 8.44 (s, 1H), 8.17-8.15 (m, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.10–6.94 (m, 3H), 4.58–4.54 (m, 2H), 3.86 (s, 3H), 3.41–3.36 (m, 2H), 2.24–2.16 (m, 5H). LCMS (M+H ⁺ ) m/z: 438.1.

Example 63: N-(2- methoxypyridine -3-day)-6-(5- methyl -1H- indazole -4-day)-9,10- dihydro -8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (compound 63) manufacturing

[0462] Step 1: Synthesis of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0463] A solution of 6-bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (100 mg, 0.32 mmol), m-CPBA (61 mg, 0.35 mmol) in DCM (20 mL) was stirred at room temperature for 30 minutes. After concentration at room temperature, the residue, 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine, was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 326.5.

[0464] Step 2: Synthesis of 6-bromo-N-(2-methoxypyridin-3-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0465] To a solution of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (60 mg, 0.18 mmol) in DMSO (5 mL) was added 2-methoxypyridin-3-amine (34 mg, 0.27 mmol). The reaction mixture was stirred at 70° C. for 16 hours. The reaction solution was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to give 6-bromo-N-(2-methoxypyridin-3-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (20 mg, 16% yield over 2 steps)

. LCMS (M+H ⁺ ) m/z: 387.1.

[0466] Step 3: Synthesis of N-(2-methoxypyridin-3-yl)-6-(5-methyl-1H-indazol-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0467] 6-Bromo-N-(2-methoxypyridin-3-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (20 mg, 0.05 mmol), 5-methyl-4-(4,4,5,5-tetramethyl-1,3 in a mixed solvent of dioxane (3 mL) and H ₂ O (0.3 mL) Pd(dppf)Cl ₂ to a solution of ,2-dioxaborolan-2-yl)-1H-indazole (20 mg, 0.08 mmol) and K ₂ CO ₃ (21 mg, 0.15 mmol). (4 mg, 0.01 mmol) was added. After addition and degassing under nitrogen gas, the reaction mixture was stirred at 100° C. for 16 hours. The reaction solution was purified by prep-HPLC to give the product, which was not pure enough. 분취형-HPLC (0.1% 포름산, 물 중 CH ₃ CN 에 의해 추가 정제를 실시하여 N-(2-메톡시피리딘-3-일)-6-(5-메틸-1H-인다졸-4-일)-9,10-디히드로-8H-피리도[1,6-a:2,3-d']디피리미딘-2-아민 (1.5 mg, 100% 순도, 포름산 염)을 황색 고체로서 수득하였다. ¹ H NMR (400 MHz, CD ₃ OD): δ 9.00 (s, 1H), 8.59 (dd, J = 7.6, 1.2 Hz, 1H), 8.52 (s, 1H), 8.06 (s, 1H), 7.95 (dd, J = 4.8, 1.2 Hz, 1H), 7.85 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.09 (dd, J = 7.6, 4.8 Hz, 1H), 4.70-4.68 (m, 2H), 4.07 (s, 3H), 3.53-3.51 (m, 2H), 2.35-2.32 (m, 5H). LCMS (M+H ⁺ ) m/z: 439.1.

Example 64:3 - methyl -1-(4-(2-( methylamino )-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -6-yl) phenyl) pyrazin-2 (1H) -one (compound 64) manufacturing

[0468] Step 1: Synthesis of 1-(4-iodophenyl)-3-methylpyrazin-2(1H)-one

[0469] CuI (130 mg, 0.68 mmol), K ₃ PO ₄ (962 mg, 4.54 mmol), N ¹ ,N ² -dimethylethane-1,2-diamine (120 mg, 1.36 mmol) and 1,4-diamine in a solution of 3-methylpyrazin-2(1H)-one (500 mg, 4.54 mmol) in dioxane (15 mL). Iodobenzene (643 mg, 2.27 mmol) was added at room temperature, purged and then degassed with N ₂ three times, and the mixture was stirred at 110° C. for 18 hours. The solvent was removed and purified by column chromatography on silica gel (PE/EtOAc = 3:1) to give 1-(4-iodophenyl)-3-methylpyrazin-2(1H)-one (280 mg, 47% yield). LCMS (M+H ⁺ ) m/z: 313.0

[0470] Step 2: Synthesis of 3-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2(1H)-one

[0471] Pd(dppf)Cl ₂ (150 mg, 0.205 mmol), KOAc (300 mg, 3.1 mmol) and 4,4,4',4',5,5,5',5'-octamethyl- 2,2′-Bi(1,3,2-dioxaborolane) (536 mg, 2.1 mmol) was added at room temperature, purged and degassed with N ₂ three times and the mixture was stirred at 105° C. for 18 hours. The solvent was removed and purified by column chromatography on silica gel (PE/EtOAc = 3:1) to give 3-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2(1H)-one (250 mg, 76% yield). LCMS (M+H ⁺ ) m/z: 313.3

[0472] Step 3: Synthesis of 6-bromo-2-(methylsulfonyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0473] A mixture of 6-bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (700 mg, 2.2 mmol) and oxone (3.47 g, 5.65 mmol) in CH ₃ CN (10 mL) and water (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and then purified by prep-HPLC (0.1% TFA, CH ₃ CN in water) to give 6-bromo-2-(methylsulfonyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidine (crude, 1.1 g). LCMS (M+H ⁺ ) m/z: 343.0

[0474] Step 4: Synthesis of 6-bromo-N-methyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0475] To a mixture of 6-bromo-2-(methylsulfonyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (1.1 g, 3.2 mmol) in THF (10 mL) in THF (5 mL, _2M ) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue was purified by column chromatography on silica gel (DCM/MeOH = 20:1) to give 6-bromo-N-methyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (220 mg, 23% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 294.0

[0476] Step 5: Synthesis of 3-methyl-1-(4-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)phenyl)pyrazin-2(1H)-one

[0477] Pd(dppf)Cl ₂ to a solution of 6-bromo-N-methyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (40 mg, 0.136 mmol) in dioxane/H 2 O ( ₅ mL). (10 mg, 0.013 mmol), Na ₂ CO ₃ (30 mg, 0.272 mmol) and 3-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2(1H)-one (51 mg, 0.168 mmol) were added at room temperature and purged then degassed with N ₂ three times, the mixture was stirred at 90 °C for 18 hours. The mixture was diluted with water (50 mL) then extracted with EtOAc (50 mL x 3). The reaction mixture was concentrated in vacuo to remove the solvent and then purified by preparative-HPLC (0.1% TFA, CH ₃ CN in water) to afford 3-methyl-1-(4-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)phenyl)pyrazin-2(1H)-one (10 mg, 18% yield, TFA salt) as yellow Obtained as a solid. ^1H NMR (400 MHz, CD ₃ OD): δ 8.77 (s, 1H), 7.94 (s, 1H), 7.67 (s, 4H), 7.47 (d, J = 4.4 Hz, 1H), 7.35 (d, J = 4.8 Hz, 1H), 4.69-4.66 (m, 2H), 3 .60-3.57 (m, 2H), 3.09 (s, 3H), 2.47 (s, 3H), 2.31-2.28 (m, 2H). LCMS (M+H ⁺ ) m/z: 400.1.

Example 65:3 -(2-((2- fluorophenyls )amino)-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -6-yl)-4-methylphenol (compound 65) manufacturing

[0478] Step 1: Synthesis of 3-(2-((2-fluorophenyl)amino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)-4-methylphenol

[0479] 6-Bromo-N-(2-fluorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (30 mg, 0.08 mmol) in dioxane (2 mL), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (28 mg, 0.12 mmol), Pd(dppf)Cl ₂ (5 mg) and K ₂ CO ₃ (33 mg, 0.24 mmol) were stirred at 70° C. for 2 h. The mixture was purified directly by preparative-HPLC (0.1% NH ₄ HCO ₃ , CH ₃ CN in water) twice to afford 3-(2-((2-fluorophenyl)amino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-6-yl)-4-methylphenol (7.0 mg, 22% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.18 (s, 1H), 9.07 (s, 1H), 8.30 (s, 1H), 7.84-7.80 (m, 1H), 7.27-7.13 (m, 3H), 6.97 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.59 (dd, J = 8.0, 2.4 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 4.01 (t, J = 6.0 Hz, 2H), 3.37 (t, J = 5.2 Hz, 2H), 2.02 (s, 3H), 1.84-1.80 (m, 2H). LCMS (M+H ⁺ ) m/z: 402.0.

Example 66: N-ethyl-6- (5- methyl -1H- indazole -4-day)-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -2-amine (compound 66) manufacturing

[0480] Step 1: Synthesis of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0481] To a solution of 6-bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (100 mg, 0.3 mmol) in DCM (4 mL) was added m-CPBA (163 mg, 0.9 mmol). The mixture was stirred at 0 °C for 3 hours. The reaction mixture was concentrated to remove DCM to give 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (crude, 242 mg) which was used directly in the next step. LCMS (M+H ⁺ ) m/z: 327.0.

[0482] Step 2: Synthesis of 6-bromo-N-ethyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0483] A mixture of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (242 mg, crude), ethaneamine hydrochloride (58 mg, 0.9 mmol), Et ₃ N (165 mg, 1.5 mmol) in DMSO (4 mL) was stirred at 70 °C for 3 h. The reaction mixture was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ , CH ₃ CN in water) to give 6-bromo-N-ethyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-amine (38 mg, 41% yield). LCMS (M+H ⁺ ) m/z: 308.0.

[0484] Step 3: Synthesis of N-ethyl-6-(5-methyl-1H-indazol-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0485] 6-Bromo-N-ethyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (28 mg, 0.09 mmol), 5-methyl-1H-indazol-4-ylboronic acid (19 mg, 0.12 mmol), K ₂ CO ₃ (37 mg, 0.27 mmol), and Pd (dppf )Cl ₂ (7 mg, 10 mol%) was suspended in 1,4-dioxane (2 mL) and H ₂ O (0.5 mL) under N ₂ . The reaction mixture was refluxed for 3-5 hours. The reaction mixture was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ , H ₃ CN in water) to afford N-ethyl-6-(5-methyl-1H-indazol-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-amine (4.9 mg, 15% yield) as a pale yellow solid. ^1H NMR (400 MHz, CD ₃ OD): δ 8.36 (s, 1H), 7.76 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 4.40-4.34 (m, 2H), 3.54-3.48 (m, 2H), 3.44–3.39 (m, 2H), 2.30 (s, 3H), 2.09–2.05 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 360.1.

Example 67:3 -((6-(2- chlorophenyl )-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -2-yl)amino)pyridin-4-ol (compound 67) manufacturing

[0486] Step 1: Synthesis of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0487] To a solution of 6-bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (150 mg, 0.5 mmol) in DCM (4 mL) was added m-CPBA (130 mg, 0.75 mmol). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated to remove DCM to give 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (crude, 290 mg) which was used directly in the next step. LCMS (M+H ⁺ ) m/z: 327.0.

[0488] Step 2: Synthesis of 6-bromo-N-(4-methoxypyridin-3-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0489] A mixture of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (290 mg, crude, 0.5 mmol) and 4-methoxypyridin-3-amine (186 mg, 1.5 mmol) in DMSO (4 mL) was stirred at 35°C for 0.5 h. The reaction mixture was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ , CH ₃ CN in water) to give 6-bromo-N-(4-methoxypyridin-3-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-amine (42 mg, 22% yield over 2 steps). LCMS (M+H ⁺ ) m/z: 387.0.

[0490] Step 3: Synthesis of 3-((6-(2-chlorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)amino)pyridin-4-ol

[0491] 6-Bromo-N-(4-methoxypyridin-3-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (24 mg, 0.06 mmol), (2-chlorophenyl)boronic acid (12 mg, 0.08 mmol), K ₂ CO ₃ (25 mg, 0.18 mmol), and Pd ( dppf)Cl ₂ (5 mg, 10 mol %) was suspended in THF (2 mL) and H ₂ O (0.5 mL) under the protection of N ₂ . The reaction mixture was refluxed for 3-5 hours. The reaction mixture was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ , CH ₃ CN in water) to afford 3-((6-(2-chlorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-yl)amino)pyridin-4-ol (8.5 mg, 34% yield) as a pale yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.95 (dd, J = 7.6, 2.4 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.65 (s, 1H), 7.49-7.46 (m, 1H), 7.39-7.29 (m, 4H), 6.46 (d, J = 7.6 Hz, 1H), 4.40–4.35 (m, 2H), 3.54–3.50 (m, 2H), 2.08–2.04 (m, 2H). LCMS (M+H ⁺ ) m/z: 405.

Example 68:6 -(2,4- dichlorophenyl )-N-(2- Fluoro -4-(piperazin-1-yl)phenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (compound 68) manufacturing

[0492] Step 1: Synthesis of 3-((6-(2,4-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)propan-1-ol

[0493] A solution of 7-chloro-6-(2,4-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine (5.5 g, 15.4 mmol) and 3-aminopropan-1-ol (20 mL) was stirred at 90 °C for 2 h under N ₂ . The mixture was added to water (100 mL) and filtered to give 3-((6-(2,4-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)propan-1-ol (6.8 g, crude) as a yellow solid. LCMS (M+H ⁺ ) m/z: 395.1.

[0494] Step 2: Synthesis of 6-(2,4-dichlorophenyl)-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0495] To a solution of 3-((6-(2,4-dichlorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)propan-1-ol (6.7 g, 16.9 mmol) and Et ₃ N (5.1 g, 7.86 mmol) in DCM (70 mL) was added MsCl (2.91 g, 25.3 mmol). The reaction mixture was stirred at room temperature under N ₂ for 16 hours. The mixture was concentrated in vacuo and then purified by column chromatography on silica gel (DCM/MeOH = 20:1) to give 6-(2,4-dichlorophenyl)-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (9.2 g, crude) as a yellow solid. LCMS (M+H ⁺ ) m/z: 377.1.

[0496] Step 3: Synthesis of 6-(2,4-dichlorophenyl)-2-(methylsulfonyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0497] To a solution of 6-(2,4-dichlorophenyl)-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (2.0 g, 5.30 mmol) in CH ₃ CN (10 mL) and H ₂ O (10 mL) was added Oxone (3.2 g, 5.30 mmol). The reaction mixture was stirred at room temperature under N ₂ for 2 hours. The mixture was purified by preparative-HPLC (0.1% HCl) to give 6-(2,4-dichlorophenyl)-2-(methylsulfonyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (500 mg, 23% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 409.1.

[0498] Step 4: Synthesis of tert-butyl 4-(4-((6-(2,4-dichlorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate

[0499] To a solution of 6-(2,4-dichlorophenyl)-2-(methylsulfonyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (150 mg, 0.36 mmol) in DMSO (3 mL) was added tert-butyl 4-(4-amino-3-fluorophenyl)piperazine-1-carboxylate (86 mg, 0.2 9 mmol) was added. The reaction mixture was stirred at 120° C. for 2 h under N ₂ . The mixture was added to water, extracted with EtOAc (10 mL x 3), washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , concentrated and purified by prep-TLC (MeOH/DCM = 1:20) to yield tert-butyl 4-(4-((6-(2,4-dichlorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d'] Dipyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (10 mg, 4% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 624.3.

[0500] Step 5: Synthesis of 6-(2,4-dichlorophenyl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0501] To a solution of tert-butyl 4-(4-((6-(2,4-dichlorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)amino)-3-fluorophenyl)piperazine-1-carboxylate (10 mg, 0.016 mmol) in MeOH (1 mL) was added with HCl/dioxane (2 mL, 3M) was added. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated in vacuo and then purified by prep-HPLC (0.1% TFA, CH ₃ CN in water) to afford 6-(2,4-dichlorophenyl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (4.5 mg, 54% yield, TFA salt) as yellow Obtained as a solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.96 (br, 1H), 8.05-8.03 (m, 1H), 7.89-7.87 (m, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.52-7.47 (m, 2H), 6.99 (d, J = 14.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.44–4.26 (m, 2H), 3.46–3.43 (m, 6H), 3.26–3.25 (m, 4H), 2.20–2.05 (m, 2H). LCMS (M+H ⁺ ) m/z: 524.2.

Example 69:6 -(2,4- dichlorophenyl )-N-(3- Fluoro -4-(piperazin-1-yl)phenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (compound 69) manufacturing

[0502] Step 1: Synthesis of tert-butyl 4-(4-((6-(2,4-dichlorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate

[0503] To a solution of 6-(2,4-dichlorophenyl)-2-(methylsulfonyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (170 mg, 0.42 mmol) in DMSO (4 mL) was added tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (122 mg, 0. 42 mmol) was added. The reaction mixture was stirred at 120 °C for 2 h under N ₂ . The mixture was added to water, extracted with EtOAc (10 mL x 3), washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , concentrated and then purified by preparative-TLC (DCM/MeOH = 20:1) to yield tert-butyl 4-(4-((6-(2,4-dichlorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3- Obtained d′]dipyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (10 mg, 4% yield) as a black solid. LCMS (M+H ⁺ ) m/z: 624.1.

[0504] Step 2: Synthesis of 6-(2,4-dichlorophenyl)-N-(3-fluoro-4-(piperazin-1-yl)phenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

To a solution of tert-butyl 4-(4-((6-(2,4-dichlorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (10 mg, 0.016 mmol) in MeOH (1 mL), HCl/dioxane (3 mL, 3M) was added. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated and purified by preparative-HPLC (0.1% TFA, CH ₃ CN in water) to afford 6-(2,4-dichlorophenyl)-N-(3-fluoro-4-(piperazin-1-yl)phenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (8.1 mg, 67% yield, TFA salt) as a yellow solid was obtained as ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.04 (s, 1H), 8.07 (s, 1H), 7.87 (t, J = 2.0 Hz, 1H), 7.72 (d, J = 14.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.60-7.57 (m, 1H), 7.54-7.52 (m, 1H), 7.17 (t, J = 9.2 Hz, 1H), 4.62-4.46 (m, 2H), 3.49-3.45 (m, 2H), 3.28-3.22 (m, 8H), 2.29-2.10 (m, 2H). LCMS (M+H ⁺ ) m/z: 524.2.

Example 70:6 -(2,4- dichlorophenyl )-N-(2- methoxy -6-(piperazin-1-yl)pyridin-3-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (compound 70) manufacturing

[0506] Step 1: Synthesis of tert-butyl 4-(5-((6-(2,4-dichlorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate

[0507] To a solution of 6-(2,4-dichlorophenyl)-2-(methylsulfonyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (170 mg, 0.42 mmol) in DMSO (4 mL) was added tert-butyl 4-(5-amino-6-methoxypyridin-2-yl)piperazine-1-carboxylate (12 8 mg, 0.42 mmol) was added. The reaction mixture was stirred at 120° C. for 2 h under N ₂ . The mixture was added to water, extracted with EtOAc (10 mL x 3), washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , concentrated in vacuo and purified by preparative-TLC (DCM/MeOH = 20 : 1) to yield tert-butyl 4-(5-((6-(2,4-dichlorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3 Obtained -d']dipyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate (100 mg, crude) as a black solid. LCMS (M+H ⁺ ) m/z: 637.3.

[0508] Step 2: Synthesis of 6-(2,4-dichlorophenyl)-N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0509] To a solution of tert-butyl 4-(5-((6-(2,4-dichlorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxylate (100 mg, crude) in MeOH (2 mL), HCl/dioxane ( 3 mL, 3M) was added. The mixture was stirred at room temperature for 2 hours under N ₂ . The residue was concentrated and purified by preparative-HPLC (0.1% TFA, CH ₃ CN in water) to give 6-(2,4-dichlorophenyl)-N-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (3.8 mg, 3% yield, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.00-8.80 (m, 1H), 8.02 (s, 1H), 7.91-7.87 (m, 1H), 7.64 (dd, J = 8.4, 2.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.35 (br, 1H), 6.51 (d, J = 8.0 Hz, 1H), 4.38-4.24 (m, 2H), 3.87 (s, 3H), 3.79-3.70 (m, 4H), 3.43-3.37 (m, 2H), 3.28-3.23 (m, 4H), 2.14-2.09 (m, 2H). LCMS (M+H ⁺ ) m/z: 537.2.

Example 71:1 -(3- Chloro -4-(2-( methylamino )-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -6-yl)phenyl)-3-methylimidazolidin-2-one (compound 71) manufacturing

[0510] Step 1: Synthesis of 1-(4-bromo-3-chlorophenyl)-3-methylimidazolidin-2-one

[0511] Pd ₂ (dba) ₃ (91.5 mg, 1 mmol), Cs ₂ CO ₃ (6.5 g, 20 mmol), XantPhos (1.156 g, 2 mmol) and 1-bromo-2-chloro-4-iodobenzene ( 6.34 g, 20 mmol) was added at room temperature, purged and then degassed with N ₂ 3 times, and the mixture was stirred at 100° C. for 4 hours. The mixture was diluted with water (50 mL) then extracted with EtOAc (50 mL x 3). The residue was purified by column chromatography on silica gel (PE/EtOAc = 3:1) to give 1-(4-bromo-3-chlorophenyl)-3-methylimidazolidin-2-one (1.3 g, 86% yield). LCMS (M+H ⁺ ) m/z: 290.6.

[0512] Step 2: Synthesis of 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylimidazolidin-2-one

[0513] Pd(dppf)Cl ₂ to a solution of 1-(4-bromo-3-chlorophenyl)-3-methylimidazolidin-2-one (1.0 g, 10.0 mmol) in dioxane (10 mL). (1.3 g, 4.49 mmol), KOAc (1.32 g, 13.4 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.4 g, 13.4 mmol) were added at room temperature, purged and then degassed with N ₂ three times, and the mixture was 18 h at 100 °C. Stir. The mixture was diluted with water (50 mL) then extracted with EtOAc (50 mL x 3). The residue was purified by column chromatography on silica gel (PE/EtOAc = 3:1) to give 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylimidazolidin-2-one (250 mg, 21% yield). LCMS (M+H ⁺ ) m/z: 337.5

[0514] Step 3: Synthesis of 1-(3-chloro-4-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)phenyl)-3-methylimidazolidin-2-one

[0515] Pd(dppf)Cl ₂ (32 mg, 0.044 mmol), Na ₂ CO ₃ ( 140 mg, 1.32 mmol) and 6-bromo-N- _methyl -9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-amine (131 mg, 0.44 mmol) were added at room temperature, purged and degassed with N ₂ three times, and the mixture was stirred at 100° C. for 18 hours. The mixture was diluted with water (50 mL) then extracted with EtOAc (50 mL x 3). The reaction mixture was concentrated in vacuo to remove the solvent and then purified by prep-HPLC (0.1% HCl) to afford 1-(3-chloro-4-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)phenyl)-3-methylimidazolidin-2-one (15.2 mg, 10% yield, HCl salt) as a white solid. did ¹ H NMR (400 MHz, CD ₃ OD): δ 8.82 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.88 (s, 1H), 7.60 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 4.70-4.57 (m , 2H), 3.94–3.90 (m, 2H), 3.63–3.56 (m, 4H), 3.10 (s, 3H), 2.90 (s, 3H), 2.38–3.20 (m, 2H). LCMS (M+H ⁺ ) m/z: 424.1.

Example 72:1 -(3- Chloro -4-(2-( methylamino )-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -6-yl) phenyl) -3-methylpyridin-2 (1H) -one (compound 72) manufacturing

[0516] Step 1: Synthesis of 1-(4-bromo-3-chlorophenyl)-3-methylpyridin-2(1H)-one

[0517] Pd ₂ (dba) ₃ (460 mg, 0.5 mmol), Cs ₂ CO ₃ (3.25 g, 10 mmol), Xant-Phos (578 mg, 1 mmol) and 1-bromo-2-chloro-4-iodobenzene (1 .59 g, 5 mmol) was added at room temperature, purged and then degassed with N ₂ 3 times, and the mixture was stirred at 100° C. for 4 hours. The mixture was diluted with water (50 mL) then extracted with EtOAc (50 mL x 3). The residue was purified by column chromatography on silica gel (PE/EtOAc = 3:1) to give 1-(4-bromo-3-chlorophenyl)-3-methylpyridin-2(1H)-one (613 mg, 41% yield). LCMS (M+H ⁺ ) m/z: 297.9.

Step 2: Synthesis of 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylpyridin-2(1H)-one

[0519] Pd(dppf)Cl ₂ (150 mg, 0.205 mmol), KOAc (401 mg, 4.1 mmol) and 4,4,4',4',5,5,5',5'-octa Methyl-2,2′-bi(1,3,2-dioxaborolane) (1.56 g, 6.15 mmol) was added by purging at room temperature and degassed with N ₂ three times, then the mixture was stirred at 100° C. for 18 hours. The mixture was diluted with water (50 mL) then extracted with EtOAc (50 mL x 3). The residue was purified by prep-HPLC to give 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylpyridin-2(1H)-one (320 mg, 21% yield). LCMS (M+H ⁺ ) m/z: 345.7.

[0520] Step 3: Synthesis of 1-(3-chloro-4-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)phenyl)-3-methylpyridin-2(1H)-one

[0521] 디옥산/H ₂ O (5 mL) 중 1-(3-클로로-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-3-메틸피리딘-2(1H)-온 (100 mg, 0.34 mmol)의 용액에 Pd(dppf)Cl ₂ (25 mg, 0.034 mmol), Cs ₂ CO ₃ (331 mg, 1.02 mmol) 및 6-브로모-N-메틸-9,10-디히드로-8H-피리도[1,6-a:2,3-d']디피리미딘-2-아민 (140 mg, 0.40 mmol)을 실온에서 첨가하고 퍼징하여 N ₂ 로 3회 탈기하고, 혼합물을 100℃에서 18 시간 교반하였다. The mixture was diluted with water (50 mL) then extracted with EtOAc (50 mL x 3). The reaction mixture was concentrated to remove the solvent and purified by preparative-HPLC (0.1% TFA, CH ₃ CN in water) to yield 1-(3-chloro-4-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)phenyl)-3-methylpyridin-2(1H)-one (4.2 mg, 3% yield, TFA salt) was obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.79 (s, 1H), 7.98 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.57-7.53 (m, 3H), 6.46 (t, J = 6.8 Hz , 1H), 4.78–4.61 (m, 2H), 3.62–3.57 (m, 2H), 3.10 (s, 3H), 2.31–2.26 (m, 2H), 2.18 (s, 3H). LCMS (M+H ⁺ ) m/z: 433.1.

Example 73:1 -(3- Chloro -4-(2-( methylamino )-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -6-yl) phenyl) -3-methylpyrazin-2 (1H) -one (compound 73) manufacturing

[0522] Step 1: Synthesis of 1-(4-bromo-3-chlorophenyl)-3-methylpyrazin-2(1H)-one

[0523] CuI (130 mg, 0.68 mmol), K ₃ PO ₄ (962 mg, 4.54 mmol), N ¹ ,N ² -dimethylethane-1,2-diamine (120 mg, 1.36 mmol) and 1-bromo- 2-Chloro-4-iodobenzene (717 mg, 2.27 mmol) was added at room temperature, purged and degassed with N ₂ three times, then the mixture was stirred at 110° C. for 18 hours. The solvent was removed and the residue was purified by column chromatography on silica gel (PE/EtOAc = 1:1) to give 1-(4-bromo-3-chlorophenyl)-3-methylpyrazin-2(1H)-one (220 mg, 32% yield). LCMS (M+H ⁺ ) m/z: 299.0

[0524] Step 2: Synthesis of 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylpyrazin-2(1H)-one

[0525] To a solution of 1-(4-bromo-3-chlorophenyl)-3-methylpyrazin-2(1H)-one (220 mg, 0.73 mmol) in dioxane (10 mL) was added Pd(dppf)Cl ₂ (150 mg, 0.205 mmol), KOAc (301 mg, 3.1 mmol) and 4,4,4',4',5,5,5',5'-oxa Tamethyl-2,2′-bi(1,3,2-dioxaborolane) (360 mg, 1.5 mmol) was added at room temperature and purged then degassed with N ₂ 3 times and the mixture was stirred at 100° C. for 18 hours. The mixture was diluted with water (50 mL) then extracted with EtOAc (50 mL x 3). The residue was purified by prep-HPLC to give 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylpyrazin-2(1H)-one (250 mg, 99% yield). LCMS (M+H ⁺ ) m/z: 347.1

[0526] Step 3: Synthesis of 1-(3-chloro-4-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)phenyl)-3-methylpyrazin-2(1H)-one

[0527] Pd(dppf)Cl 2 to a solution of 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylpyrazin-2(1H)-one (71 mg, 0.2 _mmol ) in dioxane/H ₂ O (5 mL/1 mL). (12.4 mg, 0.017 mmol), Na ₂ CO ₃ (36 mg, 0.34 mmol) and 6-bromo-N-methyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (50 mg, 0.17 mmol) were added at room temperature, purged and degassed with N ₂ three times, the mixture was heated at 100 °C. Stirred for 18 hours. The mixture was diluted with water (50 mL) then extracted with EtOAc (50 mL x 3). The reaction mixture was concentrated in vacuo to remove the solvent and then purified by preparative-HPLC (0.1% TFA, CH ₃ CN in water) to give 1-(3-chloro-4-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)phenyl)-3-methylpyrazin-2(1H)-one (2.4 mg, 3% yield, TFA salt) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.88-8.78 (m, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.69-7.64 (m, 2H), 7.47 (d, J = 4.4 Hz, 1H), 7.36 (d, J = 4.4 Hz, 1H), 4.76-4.61 (m, 2H) ), 3.60–3.56 (m, 2H), 3.10–3.08 (m, 3H), 2.47 (s, 3H), 2.30–2.27 (m, 2H). LCMS (M+H ⁺ ) m/z: 434.1.

Example 74: N-(3- Chloro -4-(2-( methylamino )-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -6-yl) pyridin-2-yl) propane-1-sulfonamide (compound 74) manufacturing

[0528] Step 1. Synthesis of tert-butyl(6-bromo-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)(methyl)carbamate.

[0529] A solution of 6-bromo-N-methyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (60 mg, 0.2 mmol), Boc ₂ O (86 mg, 0.4 mmol), DMAP (122 mg, 1.0 mmol) in DCM (5 mL) was stirred at 25 °C for 18 h. The reaction mixture was purified by flash column chromatography on silica gel (DCM/MeOH = 15:1) to afford tert-butyl (6-bromo-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)(methyl)carbamate (68 mg, 86% yield) as an orange solid. LCMS (M+H ⁺ ) m/z: 394.0.

[0530] Step 2. Synthesis of tert-butyl (6-(2,3-dichloropyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)(methyl)carbamate.

[0531] tert-butyl (6-bromo-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)(methyl)carbamate (68 mg, 0.17 mmol), 2,3-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (56 mg, 0 .20 mmol), K ₂ CO ₃ (70 mg, 0.51 mmol) and Pd(dppf)Cl ₂ (12 mg, 20 mol %) were suspended in 1,4-dioxane (1 mL) and water (0.1 mL) under N ₂ protection. The reaction mixture was refluxed at 105 °C for 3-5 hours. The reaction mixture was cooled to room temperature, filtered, dry loaded onto silica and purified by flash chromatography on silica gel (DCM/MeOH = 15:1) to give tert-butyl (6-(2,3-dichloropyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)(methyl)carbamate (46 mg, 58% yield). LCMS (M+H ⁺ ) m/z: 461.0.

Step 3. tert-Butyl (6-(3-chloro-2-(propylsulfonamido)pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a: Synthesis of 2,3-d']dipyrimidin-2-yl)(methyl)carbamate

[0533] tert-butyl (6-(2,3-dichloropyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)(methyl)carbamate (46 mg, 0.1 mmol), propane-1-sulfonamide (18 mg, 0.15 mmol), Cs ₂ CO ₃ (97 mg, 0.3 mmol) and Ru-phos-G4 (18 mg, 0.02 mmol) were suspended in 1,4-dioxane (2 mL) under N ₂ protection. The reaction mixture was refluxed for 18 hours. The reaction mixture was purified by flash chromatography on silica gel (DCM/MeOH = 10:1) to give tert-butyl (6-(3-chloro-2-(propylsulfonamido)pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)(methyl)carbamate (24 mg, 44% yield). LCMS (M+H ⁺ ) m/z: 548.0.

[0534] Step 4. Synthesis of N-(3-chloro-4-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)pyridin-2-yl)propane-1-sulfonamide

[0535] To a solution of tert-butyl (6-(3-chloro-2-(propylsulfonamido)pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)(methyl)carbamate (24 mg, 0.044 mmol) in 1,4-dioxane (1.0 mL) was added with 1,4-dioxane (2 mL). ) 4N HCl in saturated solution was added. After addition, the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ , CH ₃ CN in water) to afford N-(3-chloro-4-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)pyridin-2-yl)propane-1-sulfonamide (9.2 mg, 46% yield). Obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.66-8.60 (m, 1H), 8.05-8.01 (m, 1H), 8.00-7.70 (m, 1H), 6.64-6.60 (m, 1H), 4.40-4.21 (m, 2H), 3.35-3.2 2 (m, 4H), 2.92 (s, 3H), 2.10–1.96 (m, 2H), 1.75–1.64 (m, 2H), 1.00–0.92 (m, 3H). LCMS (M+H ⁺ ) m/z: 448.0.

Example 75 N-(3-(2-amino-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -6-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 75) manufacturing

[0536] Step 1: Synthesis of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine

[0537] To a solution of 6-bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (500 mg, 1.6 mmol) in DCM (5 mL) was added m-CPBA (550 mg, 3.2 mmol). The mixture was stirred at room temperature for 1 hour. The mixture is concentrated to give 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (501 mg) as a yellow solid, which is used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 326.9.

[0538] Step 2: Synthesis of 6-bromo-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0539] A mixture of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (501 mg, 1.5 mmol) in NH ₃ /THF (10 mL) was stirred at 70 °C for 16 h. The mixture was concentrated to give a crude material which was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ , CH ₃ CN in water) to give 6-bromo-9,10-dihydro-8H-pyrido[1,6-a:2,3-d′]dipyrimidin-2-amine (130 mg, 31% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 280.0.

[0540] Step 3: Synthesis of N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(trifluoromethyl)benzamide

[0541] To a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (140 mg, 0.5 mmol) in DCM (10 mL) was added 3-(trifluoromethyl)benzoyl chloride (117 mg, 0.5 mmol) and DIPEA (194 mg, 1.5 mmol). The mixture was stirred at 0 °C for 1 hour. The mixture was concentrated to give crude material. This crude material was purified by flash chromatography on column silica gel (PE/EtOAc = 20/1, v/v) to afford N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(trifluoromethyl)benzamide (124 mg, 61% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 406.0.

[0542] Step 4: Synthesis of N-(3-(2-amino-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide

[0543] To a solution of 6-bromo-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (30 mg, 0.11 mmol) in dioxane (5 mL) N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(trifluoromethyl)benzene Zamide (55 mg, 0.13 mmol), Pd(dppf)Cl ₂ (5 mg, 0.006 mmol), K ₂ CO ₃ (46 mg, 0.33 mmol) and H ₂ O (0.5 mL) were added. The mixture was stirred at 100 °C for 2 hours. The mixture was concentrated to give crude material. This crude material Unrefined material. The crude material was purified by w-HPLC (0.1 % formic acid, CH ₃ CN in water) to afford N-(3-(2-amino-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (15.5 mg, 30 % yield, formic acid salt) as a white solid. ¹ HNMR (400 MHz, DMSO-d ₆ ): δ 10.48 (s, 1H), 8.39 (s, 1H), 8.32-8.29 (m, 2H), 8.26 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.68 (dd, J = 8.0, 2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.26-7.22 (m, 2H), 7.17 (s, 2H), 4.27 (t, J = 5.4 Hz, 2H), 3.42-3.81 (m, 2H), 2.13 (s, 3H), 1.98-1.90 (m, 2H). LCMS (M+H ⁺ ) m/z: 479.0.

Example 76 N-(3-(2-amino-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (compound 76) manufacturing

[0544] Step 1: Synthesis of 4-(trifluoromethyl)picolinoyl chloride

[0545] To a solution of 4-(trifluoromethyl)picolinic acid (191 mg, 1 mmol) in DCM (5 mL) was added oxalyl dichloride (254 mg, 2 mmol). The mixture was stirred at 0 °C for 1 hour. The mixture was concentrated to give 4-(trifluoromethyl)picolinoyl chloride (200 mg, crude) as a yellow oil.

Step 2: Synthesis of N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0547] To a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (224 mg, 0.96 mmol) in DCM (10 mL) was added 4-(trifluoromethyl)picolinoyl chloride (200 mg, 0.96 mmol) and DIPEA (370 mg, 2.87 mmol). The mixture yielded 1 crude material at 0 °C. This crude material Unrefined material. A crude material w quality was obtained. The crude material was purified by flash chromatography on column silica gel (PE/EtOAc = 20/1, v/v) to afford N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide (160 mg, 41% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 407.0.

[0548] Step 3: Synthesis of N-(3-(2-amino-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide

[0549] N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)p Cholinamide (53 mg, 0.13 mmol), Pd(dppf)Cl ₂ (5 mg, 0.006 mmol), K ₂ CO ₃ (46 mg, 0.33 mmol) and H ₂ O (0.5 mL) were added. The mixture was stirred at 100 °C for 2 hours. The mixture was concentrated to give a crude material which was purified by preparative-HPLC (0.1 % formic acid, CH ₃ CN in water) to obtain N- (3-(2-amino-9,10-dihydro-8 H -pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (11.7 mg, 22 % yield, formic acid salt) was obtained as a white solid. ¹ HNMR (400 MHz, DMSO-d ₆ ): δ 10.76 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.37 (s, 1H), 8.33-8.30 (m, 2H), 8.10-8.08 (m, 1H), 7.78-7.76 (m, 2 H), 7.25–7.22 (m, 2H), 7.15 (s, 2H), 4.21–4.16 (m, 2H), 3.42–3.38 (m, 2H), 2.13 (s, 3H), 1.93–1.91 (m, 2H). LCMS (M+H ⁺ ) m/z: 480.0.

Example 77 N-(5-(2-amino-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine Preparation of -6-yl) -6-methylpyridin-3-yl) -3- (trifluoromethyl) benzamide (Compound 77)

[0550] Step 1: Synthesis of N-(5-bromo-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide

[0551] To a solution of 5-bromo-6-methylpyridin-3-amine (300 mg, 1.6 mmol) in DCM (10 mL) was added 3-(trifluoromethyl)benzoyl chloride (334 mg, 1.6 mmol) and DIPEA (330 mg, 2.56 mmol). A crude material was obtained. This crude material Unrefined material. Crude material W compound was concentrated to obtain a crude material. This crude material was purified by flash chromatography on column silica gel (PE/EtOAc = 3:1, v/v) to afford N-(5-bromo-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (331 mg, 58% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 358.9.

[0552] Step 2: Synthesis of (2-methyl-5-(3-(trifluoromethyl)benzamido)pyridin-3-yl)boronic acid

[0553] To a solution of N-(5-bromo-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (100 mg, 0.28 mmol) in dioxane (5 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (86 mg, 0.34 mmol), Pd(d ppf)Cl ₂ (10 mg, 0.014 mmol) and KOAc (83 mg, 0.84 mmol) were added. The mixture was stirred at 100° C. for 16 hours. The mixture was concentrated to give the crude product (2-methyl-5-(3-(trifluoromethyl)benzamido)pyridin-3-yl)boronic acid which was used directly in the next step. LCMS (M+H ⁺ ) m/z: 325.0.

[0554] Step 3: Synthesis of N-(5-(2-amino-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide

[0555] To a solution of (2-methyl-5-(3-(trifluoromethyl)benzamido)pyridin-3-yl)boronic acid (30 mg, 0.11 mmol) in dioxane (5 mL) was added 6-bromo-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (42 mg, 0.13 mmol), Pd(dppf )Cl ₂ (5 mg, 0.006 mmol), K ₂ CO ₃ (46 mg, 0.33 mmol) and H ₂ O (0.5 mL) were added. The mixture was stirred at 100 °C for 2 hours. The mixture was concentrated to give crude material. The crude material was purified by preparative-HPLC (0.1% TFA, CH ₃ CN in water) to afford N-(5-(2-amino-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (5.6 mg, 11% yield, TFA salt) as a yellow solid did ¹ HNMR (400 MHz, DMSO-d ₆ ): δ 10.87 (s, 1H), 8.96 (s, 1H), 8.88-8.85 (m, 2H), 8.33-8.22 (m, 3H), 8.03-7.98 (m, 2H), 7.93-7.81 (m, 3H), 4.49-4.42 (m, 2H), 3.60-3.40 (m, 2H), 2.35 (s, 3H), 2.18-2.14 (m, 2H). LCMS (M+H ⁺ ) m/z: 480.0.

Example 78 N-(5-(2-amino-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine Preparation of -6-yl) -2-methoxypyridin-3-yl) -2,4-difluorobenzenesulfonamide (Compound 78)

[0556] Step 1: Synthesis of (5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)boronic acid

[0557] A solution of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (100 mg, 0.4 mmol), 2,4-difluorobenzenesulfonyl chloride (102 mg, 0.48 mmol) in pyridine (5 mL) was stirred at room temperature for 16 hours. The mixture was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ , CH ₃ CN in water) to afford (5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)boronic acid (60 mg, 44% yield) as a yellow solid.

[0558] Step 2: Synthesis of N-(5-(2-amino-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0559] 6-Bromo-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (30 mg, 0.11 mmol), (5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)boronic acid (48 mg, 0.14 mmol), Pd( A solution of dppf)Cl ₂ (5 mg) and K ₂ CO ₃ (44 mg, 0.32 mmol) was stirred at 80° C. for 16 h. The mixture was purified by preparative-HPLC (0.1% formic acid, CH ₃ CN in water) to afford N-(5-(2-amino-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (9.5 mg, 18% yield, formic acid salt) as a yellow solid was obtained as ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.61 (s, 1H), 8.24 (s, 1H), 7.83-7.75 (m, 1H), 7.55-7.42 (m, 3H), 7.33-7.24 (m, 2H), 7.06 (td, J = 8.4, 2. 0 Hz, 1H), 4.28-4.26 (m, 2H), 3.75 (s, 3H), 3.35-4.33 (m, 2H), 2.02-2.00 (m, 2H). LCMS (M+H ⁺ ) m/z: 500.1.

Example 79: N-(2- fluorophenyls )-6-(1H- indazole -7-day)-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -2-amine (compound 79) manufacturing

[0560] Step 1: Synthesis of N-(2-fluorophenyl)-6-(1H-indazol-7-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0561] 6-Bromo-N-(2-fluorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (40 mg, 0.11 mmol) in dioxane (20 mL), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (4 A solution of 0 mg, 0.16 mmol), Pd(dppf)Cl ₂ (5 mg) and K ₂ CO ₃ (44 mg, 0.34 mmol) was stirred at 80° C. for 16 h. The mixture was purified twice by preparative-HPLC (0.1% NH ₄ HCO ₃ ) to give the product, which was not pure enough. Further purification by preparative-TLC (DCM/MeOH = 2:1) gave N-(2-fluorophenyl)-6-(1H-indazol-7-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (6.1 mg, 14% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.67 (s, 1H), 9.33 (s, 1H), 8.41 (s, 1H), 8.06 (s, 1H), 7.87-7.78 (m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.35-7 .10 (m, 6H), 4.12-4.09 (m, 2H), 3.37-3.36 (m, 2H), 1.94-1.90 (m, 2H). LCMS (M+H ⁺ ) m/z: 412.1.

Example 80:6 -(1H- Benzo[d]imidazole -4-day)-N-(2- fluorophenyls )-9,10- dihydro -8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (compound 80) manufacturing

[0562] Step 1: Synthesis of (1H-benzo[d]imidazol-4-yl)boronic acid

[0563] 4-bromo-1H-benzo[d]imidazole (200 mg, 1.02 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (516 mg, 2.03 mmol), Pd(dppf)Cl ₂ (20 mg) and KO in dioxane (10 mL) A solution of Ac (200 mg, 2.03 mmol) was stirred at 100 °C for 16 h. The mixture was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ , CH ₃ CN in water) to give (1H-benzo[d]imidazol-4-yl)boronic acid (30 mg, 18% yield) as a white solid.

[0564] Step 2: Synthesis of 6-(1H-benzo[d]imidazol-4-yl)-N-(2-fluorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0565] 6-Bromo-N-(2-fluorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (30 mg, 0.08 mmol), (1H-benzo[d]imidazol-4-yl)boronic acid (20 mg, 0.12 mmol), Pd(dppf)Cl ₂ in dioxane (2 mL) (5 mg) and K ₂ CO ₃ (33 mg, 0.24 mmol) was stirred at 80° C. for 5 h. The mixture was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ ) and preparative-TLC (DCM/MeOH = 3:1) to obtain 6-(1H-benzo[d]imidazol-4-yl)-N-(2-fluorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (1.8 mg, 5% yield). ) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.98 (br s, 1H), 9.24 (s, 1H), 8.36 (s, 1H), 8.14 (s, 1H), 7.84-7.81 (m, 1H), 7.62-7.60 (m, 1H), 7.32-7.11 (m, 6H), 4.11-4.08 ( m, 2H), 3.34–3.26 (m, 2H), 1.89–1.85 (m, 2H). LCMS (M+H ⁺ ) m/z: 412.1.

Example 81: N-(2- fluorophenyls )-6-(1H- Pyrazolo[3,4-b]pyridine -4-day)-9,10- dihydro -8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (compound 81) manufacturing

[0566] Step 1: Synthesis of (1H-pyrazolo[3,4-b]pyridin-4-yl)boronic acid

[0567] 4-bromo-1H-pyrazolo[3,4-b]pyridine (200 mg, 1.01 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1282 mg, 5.05 mmol), Pd(dppf)Cl ₂ in dioxane (10 mL) 100 mg) and KOAc (595 mg, 6.06 mmol) were stirred at 100 °C for 16 h. The mixture was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ , CH ₃ CN in water) to give (1H-pyrazolo[3,4-b]pyridin-4-yl)boronic acid (30 mg, 18% yield) as a white solid.

[0568] Step 2: Synthesis of N-(2-fluorophenyl)-6-(1H-pyrazolo[3,4-b]pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[0569] 6-Bromo-N-(2-fluorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (30 mg, 0.08 mmol), (1H-pyrazolo[3,4-b]pyridin-4-yl)boronic acid (20 mg, 0.12 mmol), Pd(dpp) in dioxane (2 mL) f) A solution of Cl ₂ (5 mg) and K ₂ CO ₃ (33 mg, 0.24 mmol) was stirred at 80° C. for 5 h. The mixture was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ , CH ₃ CN in water) to give the product, but the purity was not sufficiently pure. Further purification by preparative-TLC (DCM/MeOH = 3:1) gave N-(2-fluorophenyl)-6-(1H-pyrazolo[3,4-b]pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (0.8 mg, 3% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 13.54 (br, 1H), 9.35 (s, 1H), 8.48 (d, J = 4.8 Hz, 1H), 8.41 (s, 1H), 8.05 (s, 1H), 7.82-7.77 (m, 1H), 7.44 (s, 1H), 7.29-7.16 (m, 4 H), 4.07–4.04 (m, 2H), 3.33–3.30 (m, 2H), 1.90–1.88 (m, 2H). LCMS (M+H ⁺ ) m/z: 413.1.

Example 82: (4- Chloro -3-((6-(2- chlorophenyl )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-yl)amino)phenyl)methanol (compound 82) manufacturing

[0570] Step 1: Synthesis of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0571] A mixture of 6-(2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (300 mg, 0.91 mmol, 1.0 eq), m-CPBA (394 mg, 2.28 mmol, 2.5 eq) in DCM (50 mL) was heated to 0. Stir for 2 hours. The reaction was monitored by LCMS. The mixture was concentrated in vacuo to give crude product (600 mg) as a yellow solid. Crude 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine was used in the next step. LCMS (M+H ⁺ ) m/z: 345.0.

[0572] Step 2: Synthesis of 6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-ol

[0573] A mixture of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (600 mg, 1.74 mmol, 1.0 eq) in dioxane (10 mL) and H ₂ O (1 mL) was stirred at 100 °C for 1 hour. The reaction was monitored by LCMS. The mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column flash chromatography (DCM: MeOH= 10: 1, v/v) to give 6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-ol (120 mg) as a yellow solid. LCMS (M+H ⁺ ) m/z: 298.9.

[0574] Step 3: Synthesis of 2-chloro-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0575] A mixture of 6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-ol (120 mg, 0.4 mmol, 1.0 eq) in POCl ₃ (15 mL) was stirred at 120 °C for 5 h. The reaction was monitored by LCMS. The mixture was concentrated in vacuo to give the crude product. The crude product was partitioned between EA (50 mL) and H ₂ O (30 mL) and the aqueous phase was extracted twice with EA (50 mL). The organic phase was washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give 2-chloro-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (120 mg) as a yellow solid. LCMS (M+H ⁺ ) m/z: 317.1.

[0576] Step 4: Synthesis of (3-amino-4-chlorophenyl)methanol

[0577] A mixture of (4-chloro-3-nitrophenyl)methanol (1.0 g, 5.33 mmol, 1.0 eq), Fe powder (1.2 g, 21.32 mmol, 4.0 eq) and NH ₄ Cl (1.7 g, 31.99 mmol, 6.0 eq) in EtOH (30 mL) and H ₂ O (10 mL) was stirred at 85 °C for 2 h; The reaction was monitored by LCMS. The mixture was filtered and concentrated in vacuo to give the crude product. H ₂ O (10 mL) was added and the precipitate was filtered to give the product (3-amino-4-chlorophenyl)methanol (500 mg) as a white solid. LCMS (M+H ⁺ ) m/z: 158.1.

Step 5: Synthesis of (4-chloro-3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)methanol

[0579] 2-chloro-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (50 mg, 0.09 mmol, 1.0 eq), (3-amino-4-chlorophenyl)methanol (75 mg, 0.45 mmol, 3.0 eq) and HCl (6 N, 0.3 mL) of the mixture was stirred at 85 °C for 2 h and the reaction was monitored by LCMS. The mixture was purified by preparative-HPLC (0.1% FA) to give (4-chloro-3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)methanol (55.7 mg) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.29 (s, 1H), 10.15 (s, 1H), 9.01 (s, 1H), 8.27 (s, 1H), 7.69 (dd, J = 8.0, 1.2 Hz, 1H), 7.62-7.50 (m, 5H), 7.25 (dd, J = 8.0, 1.2 Hz, 1H), 5.38–5.35 (m, 1H), 4.60–4.48 (m, 4H), 4.06–4.01 (m, 2H). LCMS (M+H ⁺ ) m/z: 438.0.

Example 83: (3-((6-(2- chlorophenyl )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-yl)amino)-4-fluorophenyl)methanol (compound 83) manufacturing

[0580] Step 1: Synthesis of (3-amino-4-fluorophenyl)methanol

[0581] To a solution of (4-fluoro-3-nitrophenyl)methanol (400 mg, 2.3 mmol) in EtOH (10 mL) was added Fe (258 mg, 4.6 mmol) and NH ₄ Cl (aq, 369 mg, 6.9 mmol). The mixture was stirred at 80 °C for 2 hours. The reaction was complete by LCMS. The mixture was concentrated and extracted with EA (20 mL x 3). The organic layer was concentrated to give (3-amino-4-fluorophenyl)methanol (310 mg, 95.5% yield) as a dark green solid.

[0582] Step 2: Synthesis of (3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-4-fluorophenyl)methanol

[0583] EtOH (3 mL) (3-amino-4-fluorophenyl) methanol (18 mg, 0.126 mmol) mixture of 2-chloro-6- (2-chlorophenyl) -8,9-dihydro dazo [1 ', 2': 1,6] pyrimidine (40 mg, 0.126 mmo L) and HCL (6mol/L, 1 enemy) were added. The mixture was stirred at 85 °C for 1 hour. The mixture was concentrated and purified by prep-HPLC to afford (3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-4-fluorophenyl)methanol (27.1 mg, 51% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.32 (s, 1H), 8.32 (s, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.54-7.51 (m, 1H), 7.44-7.37 (m, 3H), 7.27 (s, 1H), 7.20 −7.15 (m, 1H), 7.09–7.07 (m, 1H), 5.24 (br, 1H), 4.48 (s, 2H), 4.02 (t, J = 8.8 Hz, 2H), 3.91 (t, J = 8.8 Hz, 2H). LCMS (M+H ⁺ ) m/z: 421.7.

Example 84 N-(2- Chloro -4-(piperazin-1-yl)phenyl)-6-(2- chlorophenyl )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-amine (compound 84) manufacturing

[0584] Step 1: Synthesis of tert-butyl 4-(3-chloro-4-nitrophenyl)piperazine-1-carboxylate

[0585] A mixture of 2-chloro-4-fluoro-1-nitrobenzene (1.75 g, 10 mmol), tert-butyl piperazine-1-carboxylate (2.42 mg, 15 mmol) and K ₂ CO ₃ (4.14 g, 30 mmol) was added to DMF (20 mL). The reaction was stirred at 100 °C for 16 hours. Detecting the reaction by LCMS showed complete completion of the reaction. The reaction was flash purified (PE: EA=3:1) to give tert-butyl 4-(3-chloro-4-nitrophenyl)piperazine-1-carboxylate (1.26 g) as a white solid. LCMS (M+H+) m/z: 342.0.

[0586] Step 2: Synthesis of tert-butyl 4-(4-amino-3-chlorophenyl)piperazine-1-carboxylate

[0587] A mixture of tert-butyl 4-(3-chloro-4-nitrophenyl)piperazine-1-carboxylate (680 mg, 2 mmol) and Fe (330 mg, 6.0 mmol) was added to NH ₄ Cl aq (3.0 mL) and EtOH (6 mL). The reaction was stirred at 80 °C for 1 hour. LCMS showed the reaction to be complete. The reaction was filtered and extracted twice with EA (50 mL). The combined organic phases were dried over Na ₂ SO ₄ and concentrated to give the product tert-butyl 4-(4-amino-3-chlorophenyl)piperazine-1-carboxylate (520 mg) as a gray solid. LCMS (M+H+) m/z: 312.0.

[0588] Step 3: Synthesis of tert-butyl 4-(3-chloro-4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

[0589] A mixture of 6-(2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 0.3 mmol) and m-CPBA (130 mg, 0.75 mmol) was added to DCM (3 mL) and the mixture was stirred at 25 °C for 0.5 h. The reaction was concentrated and tert-butyl 4-(4-amino-3-chlorophenyl)piperazine-1-carboxylate (466 mg, 1.5 mmol) in DMSO (0.5 mL) was added to the reaction mixture. The reaction was stirred at 100 °C for 2 hours. The reaction was diluted with water and extracted with EA. The combined organic phase was concentrated and the residue was purified by flash (DCM: MeOH=10:1) to afford tert-butyl 4-(3-chloro-4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (74 mg) as a gray solid. LCMS (M+H ⁺ ) m/z: 591.9.

[0590] Step 4: Synthesis of N-(2-chloro-4-(piperazin-1-yl)phenyl)-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0591] To a solution of tert-butyl 4-(3-chloro-4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (74 mg, 1.25 mmol) in DCM (4.0 mL) was added TFA (2.0 mL). . The reaction was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated and the residue was purified by HPLC (0.5%TFA) to give N-(2-chloro-4-(piperazin-1-yl)phenyl)-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (52 mg) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.14 (s, 2H), 8.94-8.90 (m, 3H), 8.25 (s, 1H), 7.69 (dd, J = 8.0, 1.2 Hz, 1H), 7.60-7.49 (m, 4H), 7.17 (d, J = 2.8 Hz, 1H), 7.03 (dd, J = 9.2, 2.8 Hz, 1H), 4.50 (br, 2H), 3.95–3.90 (m, 2H), 3.42–3.36 (m, 4H), 3.25–3.24 (m, 4H). LCMS (M+H ⁺ ) m/z: 492.0.

Example 85: N-(2- Chloro -4-(4- Methylpiperazine -1-yl) phenyl) -6- (2- chlorophenyl ) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (compound 85) manufacturing

[0592] Step 1: Synthesis of N-(2-chloro-4-(4-methylpiperazin-1-yl)phenyl)-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0593] A mixture of N-(2-chloro-4-(piperazin-1-yl)phenyl)-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (25 mg, 0.05 mmol) was added to THF (4.0 mL) followed by (CH ₂ O)n (13 mg) and NaBH(OAc )3 (32 mg, 0.015 mmol) was added to the reaction mixture. The reaction was stirred at 25° C. for 5 hours. Detection of the reaction by LCMS indicated that the reaction was complete. The reaction was poured into water (10 mL), adjusted to pH=11 with aq NaHCO ₃ and extracted with EA (15 mL x 2). The combined organic phases were dried over Na ₂ SO ₄ , concentrated and purified by HPLC to give the product N-(2-chloro-4-(4-methylpiperazin-1-yl)phenyl)-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (13.5 mg) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.00 (s, 1H), 8.28 (s, 1H), 7.54-7.53 (m, 1H), 7.51-7.37 (m, 4H), 7.28 (s, 1H), 7.01 (d, J = 2.8 Hz, 1H), 6.92 (dd, J = 8.8, 2.8 Hz, 1H), 4.01-3.99 (m, 2H), 3.91-3.89 (m, 2H), 3.17-3.15 (m, 4H), 2.50-2.49 (m, 4H), 2.24 (s, 3H). LCMS (M+H ⁺ ) m/z: 506.0.

Example 86: N-(2- Chloro -4- morpholinophenyl )-6-(2- chlorophenyl )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-amine (compound 86) manufacturing

[0594] Step 1: Synthesis of 2-chloro-4-morpholinoaniline

[0595] To a solution of 4-(3-chloro-4-nitrophenyl)morpholine (363 mg, 1.5 mmol) in EtOH (5 mL) was added Fe powder (168 mg, 3.0 mmol) and saturated aqueous NH ₄ Cl solution (1 mL) and the reaction mixture was stirred at 80 °C for 2 h. The reaction was complete by LCMS. The reaction mixture was filtered through celite and concentrated to give a yellow solid which was purified by chromatography column (DCM:MeOH=10:1) to give 2-chloro-4-morpholinoaniline (360 mg, 85% yield) as a gray solid. LCMS (M+H+) m/z: 213.1.

[0596] Step 2: Synthesis of N-(2-chloro-4-morpholinophenyl)-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0597] To a solution of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, crude) in DMSO (8 drops) was added 2-chloro-4-morpholinoaniline (360 mg, 1.7 mmol). The mixture was stirred at 110 °C for 2 hours. The reaction was complete by LCMS. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by preparative-HPLC to yield N-(2-chloro-4-morpholinophenyl)-6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (9.5 mg) as yellow Obtained as a solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.99 (br, 1H), 8.28 (br, 1H), 7.53-7.46 (m, 2H), 7.43-7.37 (m, 3H), 7.27 (br, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6. 93 (dd, J = 8.8, 2.4 Hz, 1H), 4.01–3.96 (m, 2H), 3.92–3.87 (m, 2H), 3.75–3.72 (m, 4H), 3.15–3.10 (m, 4H). LCMS (M+H ⁺ ) m/z: 493.0.

Example 87:6 -(2- chlorophenyl )-N-(4-(piperazin-1-yl)phenyl)-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-amine (compound 87) manufacturing

[0598] Step 1: Synthesis of tert-butyl 4-(4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

[0599] To a mixture of 6-(2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 0.30 mmol) in DCM (2 mL) was added m-CPBA (155 mg, 0.90 mmol) at room temperature and stirred for 20 minutes. The mixture was concentrated and tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (416 mg, 1.5 mmol) and DMSO (0.2 mL) were added. The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was purified by column chromatography (DCM: MeOH=13:1) to afford tert-butyl 4-(4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (120 mg, 71.7% yield) as a dark green oil. LCMS (M+H ⁺ ) m/z: 591.8.

[0600] Step 2: Synthesis of 6-(2-chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0601] To a solution of tert-butyl 4-(4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (120 mg, 0.22 mmol) in DCM (6 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS and TLC. Concentration gave crude material and the pH was adjusted to 7. The crude material was purified by prep-HPLC to afford 6-(2-chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (55.4 mg, 55.0% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.67 (br, 1H), 10.10 (br, 1H), 9.02 (s, 1H), 8.85 (s, 2H), 8.26 (s, 1H), 7.79 (s, 1H), 7.70 (dd, J = 7.6, 1.2 Hz; LCMS (M+H ⁺ ) m/z: 458.0.

Example 88:6 -(2- chlorophenyl )- N -(2- methoxy -4-(piperazin-1-yl)phenyl-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3- d ]Preparation of paramadan-2-amine (compound) 88

[0602] Step 1: Synthesis of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0603] To a solution of 6-(2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (400 mg, 1.2 mmol) in DCM (8 mL) was added m-CPBA (416 mg, 2.4 mmol) and the reaction mixture was stirred at 0 °C for 15 min. LCMS showed the reaction to be complete. The reaction mixture was concentrated to give 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine as a yellow solid (400 mg, crude) which was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 344.9.

[0604] Step 2: Synthesis of tert-butyl 4-(4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate

[0605] To a solution of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, crude) in DMSO (8 drops) was added tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (460 mg, 1.5 mmol) did The mixture was stirred at 120 °C for 2 hours. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by chromatography column (DCM: MeOH=20:1) to yield tert-butyl 4-(4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3- Methoxyphenyl)piperazine-1-carboxylate (45 mg) was obtained as a yellow solid. LCMS (M+H+) m/z: 588.0.

[0606] Step 3: Synthesis of 6-(2-chlorophenyl)-N-(2-methoxy-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0607] HCl (4M in dioxane) to a solution of tert-butyl 4-(4-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate (45 mg, 0.08 mmol) in dioxane (1 mL) (1 mL) was added. The mixture was stirred at 25 °C for 3 hours. LCMS showed the reaction to be complete. The mixture was concentrated to give a crude solid which was purified by preparative-HPLC to give 6-(2-chlorophenyl)-N-(2-methoxy-4-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (25.1 mg) as a red solid. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.28 (s, 1H), 8.23 (s, 3H), 7.84 (br, 1H), 7.54-7.49 (m, 1H), 7.44-7.36 (m, 3H), 7.25 (s, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.53 (d, J = 8.8, 2.4 Hz, 1H), 4.03 (d, J = 9.2 Hz, 2H), 3.92 (d, J = 9.2 Hz, 2H), 3.83 (s, 3H), 3.22 (s, 4H), 3.07 (s, 4H). LCMS (M+H ⁺ ) m/z: 488.0.

Example 89: 6 -(2- chlorophenyl )-N-(4- morpholinophenyl )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3- d ]Pyrimidine-2-amine (compound 89) manufacturing

[0608] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(4-morpholinophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0609] To a mixture of 6-(2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 0.30 mmol) in DCM (2 mL) was added m-CPBA (155 mg, 0.90 mmol) at room temperature and the reaction mixture was stirred for 20 minutes. The mixture was concentrated and 4-morpholinoaniline (267 mg, 1.5 mmol) in DMSO (0.2 mL) was added. The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was purified by preparative-HPLC to give 6-(2-chlorophenyl)-N-(4-morpholinophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (86.5 mg, 62.8% yield) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.67 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.54-7.51 (m, 1H), 7.45-7.37 (m, 3H), 7.26 (s, 1H), 6.91 (d, J = 9.2 Hz, 2H), 4.08 (t, J = 9.6 Hz, 2H), 3.93 (t, J = 9.6 Hz, 2H), 3.74 (t, J = 4.8 Hz, 4H), 3.04 (t, J = 4.8 Hz, 4H). LCMS (M+H ⁺ ) m/z: 458.9.

Example 90:6 -(2- chlorophenyl )-N-(4-(4- Methylpiperazine -1-yl) phenyl) -8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-amine (compound 90) manufacturing

[0610] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0611] A mixture of 6-(2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 0.3 mmol) and m-CPBA (130 mg, 0.75 mmol) in DCM (3 mL) was stirred at 25 °C for 0.5 h. LCMS showed the reaction to be complete. The reaction was concentrated and a solution of 4-(4-methylpiperazin-1-yl)aniline (286 mg, 1.5 mmol) in DMSO (0.5 mL) was added to the reaction mixture. The reaction was stirred at 100 °C for 2 hours. Purification by HPLC (0.5%FA) gave 6-(2-chlorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (54.2 mg) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.65 (s, 1H), 8.32 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.53-7.51 (m, 1H), 7.44-7.37 (m, 3H), 7.25 (s, 1H), 6. 89 (d, J = 9.2 Hz, 2H), 4.11–4.07 (m, 2H), 3.95–3.90 (m, 2H), 3.08–3.06 (m, 4H), 2.49–2.45 (m, 4H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 472.0.

Example 91:6 -(2- chlorophenyl )-N-(2- methoxy -4-(4- Methylpiperazine -1-yl) phenyl) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (compound 91) manufacturing

[0612] Step 1: Synthesis of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0613] To a solution of 6-(2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (400 mg, 1.2 mmol) in DCM (8 mL) was added m-CPBA (416 mg, 2.4 mmol) and the reaction mixture was stirred at 0 °C for 15 min. LCMC results indicated that the reaction was complete. The reaction mixture was concentrated to give a yellow solid (400 mg, crude) which was used in the next step without further purification. LCMS (M+H+) m/z: 362.0.

[0614] Step 2: Synthesis of 6-(2-chlorophenyl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0615] To a solution of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, crude) in DMSO (8 drops) was added 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (330 mg, 1.5 mmol). The mixture was stirred at 120 °C for 2 hours. LCMC results indicated that the reaction was complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by preparative-HPLC to give 6-(2-chlorophenyl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-2- Amine (36.5 mg) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.31 (s, 1H), 8.27 (s, 1H), 8.20 (s, 2H), 7.77 (br, 1H), 7.54-7.52 (m, 1H), 7.44-7.37 (m, 3H), 7.29 (s, 1H), 6.64 (d, J = 2.0 Hz, 1H), 6.50 (dd, J = 8.8, 2.4 Hz, 1H), 4.07 (t, J = 9.6 Hz, 2H), 3.91 (t, J = 9.6 Hz, 2H), 3.83 (d, J = 9.6 Hz, 3H), 3.21-3.08 (m, 4H), 2.54-2.52 (m, 4H), 2.27 (s, 3H). LCMS (M+H ⁺ ) m/z: 502.1.

Example 92:6 -(2- chlorophenyl )-N-(6-(4- Methylpiperazine -1-yl) pyridin-3-yl) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (compound 92) manufacturing

[0616] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0617] To a mixture of 6-(2-chlorophenyl)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (60 mg, 0.18 mmol) in DCM (2 mL) was added m-CPBA (93 mg, 0.54 mmol) at room temperature and stirred for 20 minutes. The mixture was concentrated and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (173 mg, 0.9 mmol) in DMSO (0.2 mL) was added. The reaction mixture was stirred at 100 °C for 2 hours. Purification by preparative-HPLC afforded 6-(2-chlorophenyl)-N-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (58.3 mg, 68.5% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.53-7.51 (m, 1H), 7.44-7.37 (m, 3H), 7.27 (s, 1H), 6.83 (d, J = 9.2 Hz, 1H), 4.09 (t, J = 9.6 Hz, 2H), 3.93 (t, J = 8.8 Hz, 2H), 3.42 (t, J = 4.8 Hz, 4H), 2.43 (t, J = 5.2 Hz, 4H), 2.23 (s, 3H). LCMS (M+H+) m/z: 472.7.

Example 93:6 -(2- chlorophenyl )-N-(3-(piperazin-1-yl)phenyl)-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-amine (compound 93) manufacturing

[0618] Step 1: Synthesis of tert-butyl 4-(3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

[0619] To a solution of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, crude) in DMSO (8 drops) was added tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate (554 mg, 2 mmol). The mixture was stirred at 120 °C for 2 hours. LCMC results indicated that the reaction was complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by prep-HPLC to yield tert-butyl 4-(3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carbox Silate (52 mg, 28% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 558.0.

[0620] Step 2: Synthesis of 6-(2-chlorophenyl)-N-(3-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0632] To a solution of tert-butyl 4-(3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (40 mg, 0.07 mmol) in dioxane (2 mL) was added with HCl (4M in dioxane) (1 mL, 4 mmol) was added. The mixture was stirred at 25 °C for 2 hours. LCMC results indicated that the reaction was complete. The mixture was concentrated to give a crude solid which was purified by preparative-HPLC to give 6-(2-chlorophenyl)-N-(3-(piperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (11.8 mg) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.70 (s, 1H), 8.36 (s, 1H), 7.59 (br, 1H), 7.55-7.52 (m, 1H), 7.45-7.42 (m, 1H), 7.41-7.36 (m, 1H), 7.26 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.59-6.56 (m, 1H), 6.10-6.08 (m, 2H), 4.12 (t, J = 9.6 Hz, 2H), 3.95 (t, J = 9.6 Hz, 2H), 3.72-3.66 (m, 2H), 3.59-3.57 (m, 2H), 3.08-3.06 (m, 4H). LCMS (M+H ⁺ ) m/z: 458.0.

Example 94:6 -(2- chlorophenyl )-N-(3- morpholinophenyl )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-amine (compound 94) manufacturing

[0622] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(3-morpholinophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0623] To a solution of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, crude) in DMSO (8 drops) was added 3-morpholinoaniline (356 mg, 2 mmol). The mixture was stirred at 120 for 2 hours. LCMC results indicated that the reaction was complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The organic phase collected is washed with saline (20 mL), dried, filtered, and concentrated with anhydrous NA2SO4 to obtain an undefined solid, and purified it with a sour-HPLC to 6- (2-chlorophenyl) -N- (3-mopoline nophenyl) -8,9-dihydoro [1 ', 2' 1 ', 1,6] -2-amine (47.1 mg) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 7.59 (s, 1H), 7.55-7.52 (m, 1H), 7.46-7.37 (m, 3H), 7.29 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 4.13 (t, J = 9.6 Hz, 2H), 3.95 (t, J = 9.6 Hz, 2H), 3.77-3.73 (m, 4H), 3.13-3.07 (m, 4H). LCMS (M+H+) m/z: 459.0.

Example 95:6 -(2- chlorophenyl )-N-(2- methoxy -5-(4- Methylpiperazine -1-yl) phenyl) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (compound 95) manufacturing

[0624] Step 1: Synthesis of 1-(4-methoxy-3-nitrophenyl)-4-methylpiperazine

[0625] To a solution of 4-bromo-1-methoxy-2-nitrobenzene (1.3 g, 5.65 mmol) in dioxane (15 mL) 1-methylpiperazine (565 mg, 5.65 mmol), Pd ₂ (dba) ₃ (510 mg, 0.56 mmol), Cs ₂ CO ₃ (3.67 g, 11.3 mmol) and xant-phos (323 mg, 0.56 mmol) were added and the reaction mixture was stirred at 90 °C for 3 h. LCMC results indicated that the reaction was complete. The mixture was diluted with water (20 mL) and extracted with EA (20 mL*3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by chromatography column (DCM: MeOH=20:1) to give 1-(4-methoxy-3-nitrophenyl)-4-methylpiperazine (1 g, 71% yield) as a white solid. LCMS (M+H+) m/z: 251.9.

[0626] Step 2: Synthesis of 2-methoxy-5-(4-methylpiperazin-1-yl)aniline

[0627] To a solution of 1-(4-methoxy-3-nitrophenyl)-4-methylpiperazine (1 g, 4 mmol) in EtOH (15 mL) was added Fe powder (448 mg, 8 mmol) and a saturated aqueous NHCl solution (3 mL) and the reaction mixture was stirred at 80 °C for 2 h. LCMC results indicated that the reaction was complete. The reaction mixture was filtered through celite and concentrated to give a yellow solid which was purified by preparative-HPLC to give 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (440 mg, 50% yield) as a gray solid. LCMS (M+H+) m/z: 222.1.

[0628] Step 3: Synthesis of 6-(2-chlorophenyl)-N-(2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0629] To a solution of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, crude) in DMSO (8 drops) was added 2-methoxy-5-(4-methylpiperazin-1-yl)aniline (331 mg, 1.5 mmol). The mixture was stirred at 120 °C for 2 hours. LCMC results indicated that the reaction was complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by preparative-HPLC to give 6-(2-chlorophenyl)-N-(2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-2- Amine (49 mg) was obtained as a brown solid. ¹ H NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 9.59 (s, 1H), 9.01 (s, 1H), 8.28 (s, 1H), 7.70 (dd, J = 8.0, 1.2 Hz, 1H), 7.60-7.49 (m, 3H), 7.05 (d, J = 9.2 Hz, 1H), 6.88 (dd, J = 8.8, 2.8 Hz, 1H), 4.64-4.60 (m, 2H), 4.04-4.00 (m, 2H), 3.79 (s, 3H), 3.72-3.69 (m, 2H), 3.54 (d, J = 11.2 Hz, 2H), 3.20-3.16 (m, 2H), 2.97-2.91 (m, 2H), 2.87 (s, 3H). LCMS (M+H+) m/z: 502.0.

Example 96:6 -(2- chlorophenyl )-N-(3-(4- Methylpiperazine -1-yl) phenyl) -8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-amine (compound 96) manufacturing

[0630] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0631] To a solution of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, crude) in DMSO (8 drops) was added 3-(4-methylpiperazin-1-yl)aniline (382 mg, 2 mmol). The mixture was stirred at 120 °C for 2 hours. LCMC results indicated that the reaction was complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by preparative-HPLC to give 6-(2-chlorophenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (38.2 mg) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.70 (s, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.61 (s, 1H), 7.57-7.49 (m, 1H), 7.47-7.35 (m, 3H), 7.27 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 4.12 (t, J = 9.6 Hz, 2H), 3.95 (t, J = 9.6 Hz, 2H), 3.19-3.07 (m, 4H), 2.49-2.44 (m, 4H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 471.9.

Example 97:1 -(3-((6-(2- chlorophenyl )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-yl)amino)phenyl)ethan-1-ol (compound 97) manufacturing

[0632] Step 1: Synthesis of 1-(3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)ethan-1-ol

[0633] To a solution of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, crude) in DMSO (8 drops) was added 1-(3-aminophenyl)ethan-1-ol (274 mg, 2 mmol). The mixture was stirred at 120 °C for 2 hours. LCMC results indicated that the reaction was complete. The mixture was diluted with water (10 mL), extracted with EA (10 mL*3), the combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by preparative-HPLC to give 1-(3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyridonium Obtained midin-2-yl)amino)phenyl)ethan-1-ol (24.4 mg, 20% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.85 (s, 1H), 8.39 (s, 1H), 8.16 (s, 1H), 7.92 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56-7.50 (m, 1H), 7.48-7.36 (m, 3H), 7.30 (s, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 5.14 (br, 1H), 4.69 (q, J = 6.4 Hz, 1H), 4.14 (t, J = 9.6 Hz, 2H), 3.95 (t, J = 9.6 Hz, 2H), 1.34 (d, J = 6.4 Hz, 3H). LCMS (M+H ⁺ ) m/z: 418.0.

Example 98:2 -(3-((6-(2- chlorophenyl )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-yl)amino)phenyl)propan-2-ol (compound 98) manufacturing

[0634] Step 1: Synthesis of 1-(3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)ethan-1-one

[0635] To a solution of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, crude) in DMSO (8 drops) was added 1-(3-aminophenyl)ethan-1-one (270 mg, 2 mmol). The mixture was stirred at 120 °C for 2 hours. LCMC results indicated that the reaction was complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by preparative-HPLC to give 1-(3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)ethan-1-one (80 mg, 64 % yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 416.0.

[0636] Step 2: Synthesis of 2-(3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)propan-2-ol

[0637] To a solution of 1-(3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)ethan-1-one (80 mg, 0.19 mmol) in THF (3 mL) was added CHMgBr (1 mL, 1 mmol). The mixture was stirred at 0 °C for 2 hours. LCMC results indicated that the reaction was complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were dried over brine (20 mL), anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by prep-HPLC to give 2-(3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)propan-2-ol (14.4 mg) as a yellow solid did ¹ H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.55-7.50 (m, 1H), 7.44 (dt, J = 4.0, 3.6 Hz, 1H), 7.41-7.36 (m, 2H), 7.30 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 4.96 (s, 1H), 4.14 (t, J = 9.6 Hz, 2H), 3.95 (t, J = 9.6 Hz, 2H), 1.44 (s, 6H). LCMS (M+H ⁺ ) m/z: 432.0.

Example 99: ethyl 3-((6-(2- chlorophenyl )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-yl)amino)benzoate (compound 99) of manufacturing

[0638] Step 1: Synthesis of 3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)benzoate

[0639] To a solution of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (50 mg, 0.145 mmol) and ethyl 3-aminobenzoate (479 mg, 2.9 mmol) in DMSO (10 drops) is added TEA (29 mg, 0.29 mmol) did The mixture was stirred at 100 °C for 2 hours. The mixture was purified by prep-HPLC to afford 3-((6-(2-chlorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)benzoate (17.5 mg, 27% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.14 (s, 1H), 8.77 (s, 1H), 8.43 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.60 -7.52 (m, 2H), 7.47-7.37 (m, 4H), 7 .33 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.19 (t, J = 9.6 Hz, 2H), 3.98 (t, J = 9.6 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 446.0.

Example 100:6 -(2- chlorophenyl )-N-(6- Morpholinopyridine -3-day)-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-amine (compound 100) manufacturing

[0640] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(6-morpholinopyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0641] To a solution of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, crude) in DMSO (8 drops) was added 6-morpholinopyridin-3-amine (358 mg, 2 mmol). The mixture was stirred at 120 °C for 2 hours. LCMC results indicated that the reaction was complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by preparative-HPLC to give 6-(2-chlorophenyl)-N-(6-morpholinopyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (38.3 mg, 2 9% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.54-7.51 (m, 1H), 7.44-7.36 (m, 3H), 7.27 (s, 1H), 6.84 (d, J = 9.2 Hz, 1H), 4.09 (t, J = 9.6 Hz, 2H), 3.93 (t, J = 9.6 Hz, 2H), 3.71 (t, J = 4.8 Hz, 4H), 3.37 (t, J = 4.8 Hz, 4H). LCMS (M+H ⁺ ) m/z: 460.0.

Example 101: 6 -(2- chlorophenyl )-N-(6- methylpyridine -3-day)-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-amine (compound 101) manufacturing

[0640] Step 1: Synthesis of 6-(2-chlorophenyl)-N-(6-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0641] To a solution of 6-(2-chlorophenyl)-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, crude) in DMSO (8 drops) was added 6-methylpyridin-3-amine (162 mg, 1.5 mmol). The mixture was stirred at 120 °C for 2 hours. LCMC results indicated that the reaction was complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by preparative-HPLC to give 6-(2-chlorophenyl)-N-(6-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (29.9 mg) as a yellow solid. did ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.93 (s, 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.39 (s, 1H), 8.17 (s, 1H), 8.11 (dd, J = 8.4, 2.4 Hz, 1H), 7.54-7.52 (m, 1H), 7.45-7.38 (m, 3H), 7.30 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 4.12 (t, J = 9.6 Hz, 2H), 3.94 (t, J = 9.6 Hz, 2H), 2.41 (s, 3H). LCMS (M+H ⁺ ) m/z: 389.0.

Example 102:6 -(2,4- dichlorophenyl )-N-(1- methyl -1H- pyrazole -4-day)-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-amine (compound 102) manufacturing

[0644] Step 1: Synthesis of 6-bromo-N-(6-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-2-amine

[0645] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (6.0 g, 19.17 mmol) in DMSO (30 mL) was added 1-methyl-1H-pyrazol-4-amine (2.8 g, 28.75 mmol) and the mixture was heated at 120 °C. Stir for 2 hours. The reaction mixture was removed in vacuo. The residue was purified by column chromatography (DCM:MeOH=20:1) to give 6-bromo-N-(6-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-2-amine (6.0 g, 85.7% yield) as a brown solid. LCMS (M+H+) m/z: 346.0 and 348.0.

[0646] Step 2: Synthesis of 6-(2,4-dichlorophenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0647] To a solution of 6-bromo-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (100 mg, 0.29 mmol) in dioxane/H ₂ O (6 mL/2 mL) was added to 2-(2,4-dichlorophenyl)-4,4,5,5- Tetramethyl-1,3,2-dioxaborolane (55 mg, 0.29 mmol), Pd(dppf)Cl ₂ (21 mg, 0.029 mmol), Cs ₂ CO ₃ (283 mg, 0.84 mmol) were added. The mixture was stirred at 90° C. for 2 h under N2. The reaction mixture was concentrated and the residue was purified by prep-HPLC (0.1% FA) to give 6-(2,4-dichlorophenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (11.2 mg, 9.4% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.87 (s, 0.7H), 9.73 (s, 0.3H), 8.33 (s, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.69 (s, 1H), 7.56 (s, 1H), 7.4 7 (s, 2H), 7.30 (s, 1H), 4.22–4.18 (m, 2H), 3.95 (t, J = 8.4 Hz, 2H), 3.82 (s, 3H). LCMS (M+H ⁺ ) m/z: 412.1.

Example 103: 6 -(2,4- dichlorophenyl )-N-(1-(1- Methylpiperidine -4-day)-1H- pyrazole Preparation of -4-yl) -8,9-dihydroimidazo [1', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (Compound 103)

[0648] Step 1: Synthesis of 6-bromo-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0649] A mixture of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg 0.32 mmol) and 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (86 mg 0.48 mmol) in DMSO (3 mL) at 120°C Stirred for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (30 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, concentrated and the residue was purified by column chromatography on silica gel (DCM/MeOH=8/1) to give 6-bromo-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d Obtained ]pyrimidin-2-amine (120 mg, 87.3% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 429.1 and 431.1.

[0650] Step 2: Preparation of 6-(2,4-dichlorophenyl)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0651] To a solution of 6-bromo-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (120 mg, 0.28 mmol) in dioxane/H ₂ O (10 mL/1 mL) (2,4-dichlorophenyl ) Boronic acid (59 mg, 0.31 mmol), Pd(dppf)Cl ₂ (21 mg, 0.029 mmol), Cs ₂ CO ₃ (283 mg, 0.84 mmol) were added. The mixture was stirred at 90° C. for 4 h under N ₂ , concentrated, and the residue was purified by preparative-HPLC (0.1% FA) followed by preparative-HPLC (0.1% NH ₃ ^. H ₂ O) to obtain 6-(2,4-dichlorophenyl)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1′, Obtained 2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (7.5 mg, 5.4% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.87-9.72 (m, 1H), 8.32 (s, 1H), 7.97-7.95 (m, 1H), 7.70 (s, 1H), 7.60-7.53 (m, 1H), 7.47 (s, 2H), 7.29 (s, 1H), 4.18-4.15 (m, 2H), 4.07-3.96 (m, 2H), 2.89-2.87 (m, 2H), 2.23 (s, 3H), 2.08-2.06 (m, 2H), 1.97-1.92 (m, 4H). LCMS (M+H ⁺ ) m/z: 495.2.

Example 104: N-(6-(5-amino-2-bromo-4-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-N-methyl-4-(trifluoromethyl)picolinamide (compound 104) manufacturing

[0652] Step 1: Synthesis of 6-(3-amino-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0653] 6-Bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (400 mg, 1.43 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)a in dioxane (15 mL) and water (3 mL) A mixture of niline (510 mg, 2.1 mmol), Cs ₂ CO ₃ (1.4 g, 4.29 mmol) and Pd(dppf)Cl ₂ (100 mg, 0.143 mmol) was stirred at 110° C. under N ₂ for 18 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH = 10/1) to give 6-(3-amino-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (248 mg, 56% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 311.3.

[0654] Step 2: 6-(5-Amino-2-bromo-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido Synthesis of [2,3-d]pyrimidin-2-amine

[0655] To a mixture of 6-(3-amino-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (240 mg, 0.774 mmol) in DMF (5 mL) was added NBS (137 mg, 0.774 mmol). The solution was stirred at room temperature under N ₂ for 2 hours. Water was added and the mixture was extracted twice with EA. The combined extracts were concentrated and purified by flash chromatography to afford 6-(5-amino-2-bromo-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (78 mg, 26% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 389.0, 391.0.

[0656] Step 3: Synthesis of N-(6-(5-amino-2-bromo-4-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-N-methyl-4-(trifluoromethyl)picolinamide

[0657] A solution of 4-(trifluoromethyl)picolinic acid (22 mg, 0.116 mmol) and HATU (58 mg, 0.154 mmol) in DMF (3 mL) was stirred at room temperature for 15 minutes, then 6-(5-amino-2-bromo-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] Pyrimidine-2-amine (30 mg, 0.077 mmol) and DIEA (0.038 mL, 0.231 mmol) were added. The reaction was stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by prep-HPLC (0.1% TFA) to afford N-(6-(5-amino-2-bromo-4-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-N-methyl-4-(trifluoromethyl)picolinamide (5.4 mg, 12.5% yield) as a yellow solid. . ¹ H NMR (400 MHz, CD3OD): δ 8.89 (s, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.78 (d, J = 5.2 Hz, 1H), 7.41 (d, J = 10.4 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.53–4.39 (m, 2H), 4.19–4.12 (m, 2H), 3.82 (s, 3H). LCMS (M+H ⁺ ) m/z: 562.4.

Example 105 N-(4- methyl -3-(2-( methylamino )-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 105) manufacturing

[0658] The preparation of 6-bromo-N-methyl-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine and N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide is described in Example 76 and Example 74. has been

[0659] Step 1: Synthesis of N-(4-methyl-3-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0660] 디옥산 (20 mL) 및 H ₂ O (2 mL) 중 6-브로모-N-메틸-9,10-디히드로-8H-피리도[1,6-a:2,3-d']디피리미딘-2-아민 (100 mg, 0.34 mmol, 1.0 eq), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린아미드 (207 mg, 0.51 mmol, 1.5 eq), K ₂ CO ₃ (141 mg, 1.02 mmol, 3.0 eq) 및 Pd(dppf)Cl ₂ (10 mg)의 혼합물을 100℃에서 2시간 동안 교반하였다. The mixture was purified by preparative-HPLC (0.1% FA) and (0.1% NH4HCO3) to afford N-(4-methyl-3-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (25.9 mg, 15.9 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.70 (s, 1H), 9.03-9.01 (m, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 8.08 (d, J = 5.2 Hz, 1H), 7.74-7.72 (m, 2H), 7.40-7.29 (m, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.03 (s, 1H), 4.19-4.02 (m, 2H), 3.39 (s, 2H), 2.87 (d, J = 4.4 Hz, 3H), 2.13 (s, 3H), 1.86 (s, 2H). LCMS (M+H ⁺ ) m/z: 494.0.

Example 106 N-(3-(2-amino-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (compound 106) manufacturing

[0661] The preparation of N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide is described in Example 76. The preparation of 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine is described in Example 26.

[0662] Step 1: Synthesis of N-(4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0663] 디옥산 (40.0 mL) 및 물 (4.0 mL) 중6-브로모-2-(메틸티오)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘 (1.83 g, 6.16 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸) 피콜린아미드 (3.0 g, 7.39 mmol), Cs ₂ CO ₃ (6.0 g, 18.48 mmol) 및 Pd(dppf)Cl ₂ (316 mg, 0.43 mmol)의 혼합물을 탈기시키고 N ₂ 를 3회 충전하고 110℃에서 16 시간 교반하였다. The reaction mixture was concentrated and purified by column chromatography (PE/EA=1/2, +0.1% TEA) to give N-(4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (2.67 g, 87% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 497.1.

[0664] Step 2: Synthesis of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0665] To a solution of N-(4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (300 mg, 0.6 mmol) in dry DCM (8.0 mL) was added m-CPBA (347 mg, 1.51 mmol). It was added at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes. The reaction mixture was concentrated under vacuum at room temperature to afford crude N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (650 mg, 100% yield) as a yellow solid which was used in the next step without purification. LCMS (M+H ⁺ ) m/z: 513.1.

[0666] Step 3: Synthesis of N-(3-(2-amino-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide

[0667] A mixture of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (170 mg, 0.33 mmol, 1.0 eq) and NH3-THF (10 mL) was stirred at 80°C for 16 hours. and the reaction was monitored by LCMS. The mixture was purified by preparative-HPLC (0.1% NH ₄ HCO ₃ ) and (0.1% FA) to give the product (26.5 mg, 17.2 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.74 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 8.19 (s, 1H), 8.09-8.08 (m, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.78-7.75 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 7.00 (s, 2H), 4.02-4.00 (m, 2H), 3.93-3.91 (m, 2H), 2.20 (s, 3H). LCMS (M+H ⁺ ) m/z: 466.0.

Example 107 N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (Compound 107)

[0668] Step 1: Synthesis of N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0669] A mixture of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (170 mg, 0.33 mmol, 1.0 eq) and MeNH ₂ -THF (10 mL) at 70°C for 1 hour Stir and monitor the reaction by LCMS. The mixture was purified by preparative-HPLC (0.1% NH4HCO3) to afford N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (22 mg, 13.8 % yield) as a yellow solid.

Example 108 N-(3-(2-(dimethylamino)-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide

[0670] Step 1: Synthesis of 6-bromo-N,N-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0671] To a solution of 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (500 mg, 1.682 mmol) in DCM (10 mL) was added m-CPBA (871 mg, 5.047 mmol). The reaction mixture was stirred at room temperature under N ₂ for 1 hour. Dimethylamine (6.0 ml) was then added to the reaction solution. The reaction mixture was stirred at room temperature under N ₂ for 16 hours. The resulting solution was washed with NH ₄ Cl and concentrated. The residue was purified by silica gel chromatography (DCM: MeOH =30:1) to give 6-bromo-N,N-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (360 mg, 72.7%) as a yellow solid. LCMS (M+H ⁺ ) m/z: 296.1.

[0672] Step 2: Synthesis of N-(3-(2-(dimethylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide

[0673] 6-Bromo-N,N-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (100 mg, 0.339 mmol), N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in dioxane (8 mL) and HO (2 mL) To a solution of -2-yl)phenyl)-4-(trifluoromethyl)picolinamide (138 mg, 0.339 mmol) and Cs2CO3 (332 mg, 1.019 mmol) was added Pd(dppf)Cl2 (25 mg, 0.034 mmol). The reaction mixture was stirred at 100° C. under N ₂ for 3 hours. The resulting solution was extracted with EA (20 mLx 3) and concentrated. The crude product was purified by preparative-TLC (DCM: MeOH=30:1) and further preparative-HPLC (0.1%/FA/CH ₃ CN/H ₂ O) to obtain N-(3-(2-(dimethylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl) Picolinamide (48.3 mg, 28.8% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.03 (d, J = 5.2Hz, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 8.08 (d, J = 4.8 Hz, 2H), 7.82 (d, J = 2 Hz, 1H), 7.76 (d, J =8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 4.07-4.02 (m, 2H), 3.94-3.89 (m, 2H), 3.18 (s, 6H), 2.20 (s, 3H); LCMS (M+H+) m/z: 496.9.

Example 109 N-(3-(2-( ethylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide formate (compound 109) manufacturing

[0674] The preparation of 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine is described in Example 26.

[0675] Step 1: Synthesis of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0676] A mixture of 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (1.0 g, 3.38 mmol) in dry DCM (20 mL) was added to m-CPBA (1.0 g, 5.07 mmol, 70% wt) at 0 °C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was diluted with saturated NaHCO3 (aq.) (20 mL) and extracted with DCM (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give crude 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine (1.2 g, crude) as a yellow solid which was used in the next step without purification. LCMS (M+H ⁺ ) m/z: 312.9 and 314.9.

[0677] Step 2: Synthesis of 6-bromo-N-ethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0678] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (crude, 765 mg, 1.01 mmol) in dry-THF (2.5 mL) was added ethanamine (0.8 mL, 1.56 mmol, 2 M in THF). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (50.0 mL) and extracted with EA (50 mL x 3). The combined organic phases were extracted with brine (50 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with EA (5.0 mL) to give 6-bromo-N-ethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (290 mg, 97% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 294.0 and 296.0.

[0679] Step 3: Synthesis of N-(3-(2-(ethylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide formate

[0680] 디옥산 (10 mL) 및 물 (1 mL) 중 6-브로모-N-에틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (150 mg, 0.51 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-4-(트리플루오로메틸)피콜린아미드 (228 mg, 0.56 mmol), Cs ₂ CO ₃ (500 mg, 1.54 mmol) 및 Pd(dppf)Cl ₂ (25 mg, 0.03 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전한 다음 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated and purified by prep-HPLC (0.1% NH ₃ -H ₂ O) to afford N-(3-(2-(ethylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide formate (20.8 mg, 8.2% yield) as a yellow solid. . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.74 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.33 (s, 1H), 8.22 (s, 1H), 8.09-8.08 (m, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.4, 2.4 Hz, 1H), 7.59-7.43 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 4.04-4.01 (m, 2H), 3.97-3.88 (m, 2H), 3.38-3.29 (m, 2H), 2.20 (s, 3H), 1.14 (s, 3H). LCMS (M+H ⁺ ) m/z: 494.3.

Example 111: N-(3-(2-((2-fluoroethyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (compound 111) manufacturing

[0681] The preparation of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide is described in Example 106.

[0682] Step 1: Synthesis of N-(3-(2-((2-fluoroethyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide

10 mg) was stirred at 60° C. for 2 h. The reaction was monitored by LCMS. The mixture was purified by prep-HPLC (0.1% FA) to give the product (19.4 mg) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) ppm: δ 10.79 (s, 1H), 9.03 (d, J = 5.6 Hz, 1H), 8.39-8.33 (m, 1H), 8.14 (s, 1H), 8.10-8.09 (m, 1H), 8.01-7.79 (m, 3H), 7.41-7.26 (m, 2H), 4.66-4.49 (m, 2H), 4.20-4.09 (m, 2H), 4.07-4.91 (m, 2H), 3.70-3.60 (m, 2H), 2.20 (s, 3H). LCMS (M+H ⁺ ) m/z: 511.9.

Example 112: N-(3-(2-((2-methoxyethyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (compound 112) manufacturing

[0684] Step 1: Synthesis of 6-bromo-N-(2-methoxyethyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0685] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (crude, 765 mg, 1.01 mmol) in dry-THF (2.5 mL) was added 2-methoxyethane-1-amine (117 mg, 1.56 mmol). The mixture was stirred at 60° C. for 2 hours. The reaction was cooled to room temperature, diluted with water (50.0 mL), and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with EA (5.0 mL) to give 6-bromo-N-(2-methoxyethyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (200 mg, 61% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 324.1 and 326.1.

[0686] Step 2: Synthesis of N-(3-(2-((2-methoxyethyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide

[0687] 디옥산 (10 mL) 및 물 (1 mL) 중 6-브로모-N-(2-메톡시에틸)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (200 mg, 0.62 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-4-(트리플루오로메틸)피콜린아미드 (275 mg, 0.68 mmol), Cs ₂ CO ₃ (600 mg, 1.85 mmol) 및 Pd(dppf)Cl ₂ (25 mg, 0.03 mmol)의 혼합물을 탈기시키고 N ₂ 로 3회 충전하고 16 시간 교반하였다. The reaction mixture was concentrated and purified by prep-HPLC (0.1% NH ₃ ^. H ₂ O) to afford N-(3-(2-((2-methoxyethyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (57.9 mg, 18% yield) as a yellow solid. was obtained as ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.76 (s, 1 H), 9.03 (d, J=4.8 Hz, 1 H), 8.33 (s, 1 H), 8.27 (s, 1 H), 8.17 (s, 1 H), 8.09 (dd, J=0.8 Hz, 3.6 Hz, 1 H), 7.83 (d, J=2.0 Hz, 1 H), 7.79 (dd, J=2.0 Hz, 8.4 Hz, 1 H), 7.58-7.47 (m, 1 H), 7.25-7.23 (m, 1 H), 4.09-4.08 (m, 1 H), 3.94-3.89 (m, 1 H), 3.50-3.49 (m, 3 H), 3.28 (s, 3 H), 2.20 (s, 3 H). LCMS (M+H ⁺ ) m/z: 524.4.

Example 113 N-(3-(2-((2-hydroxy-2- methylpropyl )amino)-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)-4- methylphenyl )-4-( trifluoromethyl ) picolinamide (compound 113) manufacturing

[0688] Step 1: Synthesis of 1-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-2-methylpropan-2-ol

[0689] To a mixture of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (205 mg, 0.65 mmol) in dry-THF (5.0 mL) was added 1-amino-2-methylpropan-2-ol (175 mg, 1.96 mmol). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated and diluted with EA (3.0 mL), stirred at room temperature for 1 hour and filtered. The collected cake was dried to give 1-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)-2-methylpropan-2-ol (115 mg, 52.3% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 337.9 and 339.9.

[0690] Step 2: Synthesis of N-(3-(2-((2-hydroxy-2-methylpropyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide

[0691] 디옥산 (5.0 mL) 및 물 (0.5 mL) 중 1-((6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)아미노)-2-메틸프로판-2-올 (115 mg, 0.34 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린아미드 (160 mg, 0.39 mmol), Cs ₂ CO ₃ (277 mg, 0.85 mmol) 및 Pd(dppf)Cl ₂ (25 mg, 0.034 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전하고 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated, diluted with water (30.0 mL) and extracted with DCM (30.0 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica column (DCM:MeOH=20:1, +0.1%NH ₃ /MeOH) to obtain N-(3-(2-((2-hydroxy-2-methylpropyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (40 mg, 22% yield). ) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ10.75 (s, 1 H), 9.03 (d, J = 5.2 Hz, 1 H), 8.33 (s, 1 H), 8.23 (s, 1 H), 8.08 (d, J=4.4 Hz, 1 H), 7.81 (d, J=1.6 Hz, 1 H), 7.77 (dd, J=2.0 Hz, 8.0 Hz, 1 H), 7.24-7.15 (m, 3 H), 4.63-4.57 (m, 1 H), 4.05-4.00 (m, 2 H), 3.92 (t, J=8.8 Hz, 2 H), 3.35 (d, J=6.4 Hz, 2 H), 2.20 (s, 3 H), 1.19-1.12 (m, 5 H). LCMS (M+H ⁺ ) m/z: 538.7.

Example 114: N-(4-methyl-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 114) manufacturing

[0692] The preparation of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine is described in Example 26.

[0693] Step 1: Synthesis of 6-bromo-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0694] A mixture of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (1.9 g, 6.07 mmol), oxetan-3-amine (2.2 g, 30.35 mmol), DIEA (1.57 g, 12.14 mmol) in THF (40.0 mL) The mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated. The residue was triturated with EA (10.0 mL) to give crude 6-bromo-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (2.0 g, 100% yield) as a yellow solid which was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 321.9 and 323.9.

[0695] Step 2: N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl) picolinamide

[0696] 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (985 mg, 4.22 mmol), HATU (2.28 g, 6.0 mmol), DIPEA (1.5 g, 1 2.0 mmol) was added. The mixture was stirred at room temperature for 1 hour. H ₂ O (100 mL) was added to the reaction mixture. The resulting mixture was filtered and the cake was washed with H ₂ O (20 mL x 3). The solid was dried to give N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl) picolinamide (1.76 g, 96% yield) as a light gray solid. LCMS (M+H ⁺ ) m/z: 407.1.

[0697] Step 3: N-(4-methyl-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0698] 6-bromo-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1, in dioxane/H ₂ O (20 mL/4 mL) N-(4-methyl-3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide (306 mg, 0.75 mmol), Pd(dppf)Cl ₂ (79 mg, 0.108 mmol), K ₂ CO ₃ (298 mg, 2.16 mmol) was added. The mixture was stirred under N ₂ at 85° C. for 16 hours. H ₂ O (100 mL) was added to the reaction mixture. The mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na ₂ SO ₄ , concentrated in vacuo and purified by prep-HPLC (1% HCOOH) to give N-(4-methyl-3-(2-( oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-6-yl)phenyl)-4-( Obtained trifluoromethyl)picolinamide (59.1 mg, 16% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.75 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.33 (s, 1H), 8.25 (s, 2H), 8.09-8.08 (m, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.78–7.76 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.17–7.17 (m, 1H), 4.96– 4.95 (m, 1H), 4.79-4.77 (m, 2H), 4.55 (t, J = 6.0 Hz, 2H), 4.06-4.01 (m, 2H), 3.94-3.89 (m, 2H), 2.20 (s, 3H). LCMS (M+H ⁺ ) m/z: 522.4.

Example 115: N-(4-methyl-3-(2-((tetrahydro-2H-pyran-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide hydrogen chloride (compound 115) manufacturing

[0699] The preparation of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide is described in Example 106.

[0700] Step 1: Synthesis of N-(4-methyl-3-(2-((tetrahydro-2H-pyran-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide hydrogen chloride

[0701] To a solution of crude N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (650 mg, 0.60 mmol) in THF (8.0 mL) was added with tetrahydro-2H-pyran-4-amine ( 305 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 16 hours, concentrated then water (80.0 mL) was added and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% HCl) to give N-(4-methyl-3-(2-((tetrahydro-2H-pyran-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide hydrogen chloride (11.0 mg, 3.1% yield) ) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.92 (s, 1H), 9.84 (s, 0.6H), 9.76 (s, 0.4H), 9.06-8.91 (m, 1H), 8.66-8.52 (m, 1H), 8.34 (s, 1H), 8.14-8.11 (m, 2H), 7.99 (s, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 4.67-4.58 (m, 2H), 4.05-3.89 (m, 6H), 3.19-3.18 (m, 1H), 2.21 (s, 3H), 1.95-1.82 (m, 2H), 1.63-1.60 (m, 2H). LCMS (M+H ⁺ ) m/z: 550.4.

Example 116: N-(3-(2-(azetidin-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (compound 116) manufacturing

[0702] Step 1: Synthesis of tert-butyl 3-((6-(2-methyl-5-(4-(trifluoromethyl)picolinamido)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1-carboxylate

[0703] To a solution of crude N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (89 mg, 0.15 mmol) in DMSO (8.0 mL) was added tert-butyl 3-aminoazetidin-1-carb Voxylate (86 mg, 0.5 mmol) was added. The mixture was stirred at 120° C. for 2 hours. The reaction mixture was diluted with water (80.0 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash (DCM:MeOH=20:1, +0.1%NH ₃ /MeOH) to give (60 mg, 67% yield) as a yellow solid.

[0704] Step 2: Synthesis of N-(3-(2-(azetidin-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide

[0705] A mixture of tert-butyl 3-((6-(2-methyl-5-(4-(trifluoromethyl)picolinamido)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1-carboxylate (60 mg, 0.1 mmol) and TFA (1 mL) in DCM (10 mL) was stirred overnight at room temperature. The resulting mixture was evaporated and the residue was purified by prep-HPLC (0.1% NH ₃ H ₂ O) to afford N-(3-(2-(azetidin-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (12 mg, 30% yield) as a white solid. obtained. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.95 (d, J = 5.2 Hz, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 7.91 (d, J = 4.4 Hz, 1H), 7.76-7.70 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 4.20-4.17 (m, 2H), 3.99 (t, J = 8.8 Hz, 4H), 3.85 (t, J = 9.2 Hz, 2H), 3.31-3.29 (m, 1H), 2.25 (s, 3H). LCMS (M+H ⁺ ) m/z: 521.1.

Example 117: N-(4-methyl-3-(2-(methylsulfonamido)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 117) manufacturing

[0706] Step 1: Synthesis of N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)methane sulfonamide

[0707] A solution of methanesulfonamide (95 mg, 1.01 mmol) in dry-THF (4.0 mL) was added followed by NaH (40 mg, 1.01 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (158 mg, 0.505 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (DCM/MeOH=10/1) to give N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)methane sulfonamide (110 mg, 63.4% yield) as a pale yellow solid. LCMS (M+H ⁺ ) m/z: 345.9 and 343.9.

[0708] Step 2: Synthesis of N-(4-methyl-3-(2-(methylsulfonamido)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0709] 디옥산 (1.5 mL) 및 물 (0.2 mL) 중 N-(6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)메탄 설폰아미드 (30 mg, 0.087 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일) 페닐)-4-(트리플루오로메틸)피콜린아미드 (39 mg, 0.096 mmol), Cs ₂ CO ₃ (85 mg, 0.261 mmol) 및 Pd(dppf)Cl ₂ (6.4 mg, 0.009 mmol)의 혼합물을 탈기하고 N ₂ 를 3회 충전하고 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated and purified by prep-HPLC (0.1% FA) to afford N-(4-methyl-3-(2-(methylsulfonamido)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (6.2 mg, 13% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.47 (s, 1H), 8.34 (s, 1H), 8.09 (d, J = 5.6 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H) ), 7.82 (d, J = 2.0 Hz, 1H), 7.45 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.21 (d, J = 5.6 Hz, 2H), 3.97 (t, J = 9.6 Hz, 2H), 3.19 (s, 3H), 2.21 (s, 3H) ). LCMS (M+H+) m/z: 544.4.

Example 118: N-(3-(2- acetamido -8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (Compound 118)

[0710] The preparation of N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide and 6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 76.

[0711] Step 1: Synthesis of N-(3-(2-amino-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide

[0712] 디옥산 (10 mL) 및 물 (1 mL) 중 6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (200 mg, 0.75 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸) 피콜린아미드 (366 mg, 0.90 mmol), Cs ₂ CO ₃ (735 mg, 2.56 mmol) 및 Pd(dppf)Cl ₂ (30 mg, 0.05 mmol)의 혼합물을 탈기시키고 N ₂ 로 3회 충전하고 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated and the residue was purified by column chromatography (DCM/MeOH=10:1) to give N-(3-(2-amino-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (200 mg, 57% yield) as a brown solid. LCMS (M+H+) m/z: 466.2.

[0713] Step 2: Synthesis of N-(3-(2-(N-acetylacetamido)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide

[ ₀₇₁₄ ] A mixture of N-(3-(2-(N-acetylacetamido)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (130 mg, 0.32 mmol) in Ac 2 O (10.0 mL) was stirred at 90 °C for 3 h. The mixture was concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10:1) to give N-(3-(2-(N-acetylacetamido)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (130 mg, 73% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 550.3.

[0715] Step 3: Synthesis of N-(3-(2-acetamido-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide

[0716] A mixture of N-(3-(2-(N-acetylacetamido)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (130 mg, 0.24 mmol) in MeOH (5.0 mL) and H ₂ O (0.5 mL) was added to NaOH (1 0 mg, 0.26 mmol). The mixture was stirred at room temperature for 16 hours, concentrated and the residue was purified by prep-TLC to give a yellow solid (40 mg) which was further purified by trituration with MeOH (2.0 mL) to N-(3-(2-acetamido-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picoline The amide (11.7 mg, 9.7% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (s, 1H), 10.47 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.09 (d, J = 4.8 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 6.0, 2.0 Hz, 1H), 7.28-7.24 (m, 2H), 4.09 (t, J = 9.2 Hz, 2H), 3.96 (t, J = 8.8 Hz, 2H), 2.29 (s, 3H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 508.3.

Example 119: N-(3-(2-(cyclopropanecarboxamido)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide (compound 119) manufacturing

[0717] The preparation of N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide is described in Example 76.

[0718] The preparation of 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine is described in Example 26.

[0719] Step 1: Synthesis of N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide

[0720] To a solution of cyclopropanecarboxamide (81 mg 0.96 mmol) in dry THF (5 mL) was added NaH (81 mg 0.96 mmol) at 0 °C and the reaction mixture was stirred for 1 hour, then 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (150 mg, 0.48 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was column chromatographed on silica gel (DCM/MeOH=10/1) to give N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide (40 mg, 25% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 334.0 and 336.0.

[0721] Step 2: Synthesis of N-(3-(2-(cyclopropanecarboxamido)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinamide formic acid

[0722] 디옥산 (5 mL) 및 물 (0.5 mL) 중 N-(6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)시클로프로판카르복스아미드 (40 mg, 0.12 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-4-(트리플루오로메틸)피콜린아미드 (54 mg, 0.13 mmol), Cs ₂ CO ₃ (116 mg, 0.36 mmol) 및 Pd(dppf)Cl ₂ (4 mg, 0.005 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전하고 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated in vacuo and then purified by column chromatography on silica gel (DCM/MeOH=10/1) to give the crude product which was purified by preparative-HPLC (0.1% FA) to N-(3-(2-(cyclopropanecarboxamido)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoro Obtained romethyl)picolinamide formic acid (15.9 mg, 23 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (s, 2 H), 9.03 (d, J=5.2 Hz, 1 H), 8.45 (s, 1 H), 8.33 (s, 1 H), 8.15 (s, 1 H), 8.09 (d, J = 4.4 Hz, 1H),, 7.86 (d, J =2.0 Hz, 1 H), 7.80 (d, J = 8.4, 2.4 Hz, 1H), 7.29 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.08 (t, J = 9.2 Hz, 2H), 3.96 (t, J = 9.2 Hz, 2H), 2.54-2.50 (m, 1H), 2.22 (s, 3H), 0.84-0.82 (m, 4H). LCMS (M+H ⁺ ) m/z: 534.8.

Example 120: N-(4-methyl-3-(5-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 120) manufacturing

[0723] Step 1: Synthesis of 5-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0724] To a mixture of 5-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.5 mmol) in DCM (6 mL) was added m-CPBA (258 mg, 1.5 mmol) at room temperature and the reaction mixture was stirred for 2 hours. The mixture was concentrated to give the crude product (300 mg) as a white solid which was used in the next step without further purification. To a mixture of the crude product (300 mg crude, 0.5 mmol) in THF (6 mL) was added 2M MeNH ₂ at room temperature and the mixture was stirred at 60° C. for 3 hours. The mixture was monitored by LCMS. The reaction mixture was poured into water, and the precipitate was filtered and dried in vacuo to give 5-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (96 mg, 78.5% yield) as a white solid. LCMS (M+H ⁺ ) m/z 191.1.

[0725] Step 2: Synthesis of 6-bromo-5-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0726] To a solution of 5-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (380 mg, 0.5 mmol) in DMF (10 mL) was added NBS (427 mg, 2.4 mmol) at room temperature and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the precipitate was filtered and dried in vacuo to give 6-bromo-5-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (360 mg, 78.5% yield) as a white solid. LCMS (M+H ⁺ ) m/z 269.0.

[0727] Step 3: Synthesis of 6-bromo-7-chloro-N,5-dimethylpyrido[2,3-d]pyrimidin-2-amine

[0728] A mixture of 6-bromo-5-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (380 mg, 0.37 mmol) in POCl ₃ (5 mL) was stirred at 110 °C for 3 h. The reaction mixture was concentrated to give 6-bromo-7-chloro-N,5-dimethylpyrido[2,3-d]pyrimidin-2-amine (287 mg, 73% yield) as a solid. LCMS (M+H ⁺ ) m/z: 286.9.

[0729] Step 4: Synthesis of 2-((6-bromo-5-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol

[0730] A mixture of 6-bromo-7-chloro-N,5-dimethylpyrido[2,3-d]pyrimidin-2-amine (287 mg, 1.0 mmol) and ethanolamine (5 mL) was stirred at 60 °C for 2 h. The reaction mixture was poured into water and extracted with DCM (20 mLx2). The combined organic phases were concentrated to afford 2-((6-bromo-5-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (230 mg, 73% yield) as a solid. LCMS (M+H ⁺ ) m/z: 312.0.

[0731] Step 5: Synthesis of 6-bromo-N,5-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0732] To a mixture of 2-((6-bromo-5-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (170 mg, 0.5 mmol), DIPEA (645 mg, 5.0 mmol) in NMP (15 mL) was added MsCl (310 mg, 2.5 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 2 hours. Water (30 mL) was added and the reaction mixture was extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL) and purified by HPLC to give 6-bromo-N,5-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (130 mg) as a solid. LCMS (M+H ⁺ ) m/z: 293.9.

[0733] Step 6: Synthesis of N-(4-methyl-3-(5-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0734] 6-브로모-N,5-디메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (30 mg, 0.1 mmol, 1.0 equiv), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린아미드 (42 mg, 0.1 mmol, 1.0 equiv), K ₂ CO ₃ (41 mg, 0.3 mmol, 3.0 equiv), 및 PdCl ₂ (dppf) (14 mg, 0.02 mmol, 20 mol %)의 혼합물을 1,4-디옥산 (2 mL) 및 H ₂ O (0.5mL)로 현탁하고 110℃에서 3 시간 교반하였다. The reaction mixture was purified by HPLC (0.5% FA) to give N-(4-methyl-3-(5-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide formate (5.6 mg) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 10.76 (s, 1H), 9.02 (d, J = 4.2 Hz, 1H), 8.47 (s, 1H), 8.32 (s, 1H), 8.16 (s, 1H), 8.07 (d, J = 4.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.70-7.60 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H,), 3.87-3.82 (m, 2H), 3.63-3.52 (m, 2H), 3.06 (s, 3H), 2.07 (s, 3H), 1.98 (s, 3H). LCMS (M+H ⁺ ) m/z: 494.0.

Example 121: N-(4-fluoro-3-(5-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 121) manufacturing

[0735] Step 1: Synthesis of N-(3-bromo-4-fluorophenyl)-4-(trifluoromethyl)picolinamide

[0736] To a solution of 4-(trifluoromethyl)picolinic acid (500 mg, 2.6 mmol) in DMF (5.0 mL) was added HATU (1.48 g, 3.9 mmol), DIEA (1.00 g, 7.8 mmol), 3-bromo-4-fluoroaniline (551 mg, 2.9 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was added to H ₂ O (20 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with brine (30 mL), Na ₂ SO ₄ , filtered and concentrated in vacuo. The obtained residue was purified by column chromatography (PE/EA = 3/1) to give N-(3-bromo-4-fluorophenyl)-4-(trifluoromethyl)picolinamide (809 mg, 86% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 363.0 and 365.0.

[0737] Step 2: Synthesis of N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0738] A mixture of N-(3-bromo-4-fluorophenyl)-4-(trifluoromethyl)picolinamide (809 mg, 2.2 mmol) in dioxane (25 mL) was added with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.68 g, 6.6 mmol), KOAc (650 mg , 6.6 mmol), Pd(dppf)Cl ₂ (160 mg, 0.22 mmol). The mixture was degassed, charged with Ar three times, and stirred at 100° C. for 3 hours. The reaction mixture was concentrated in vacuo and H ₂ O (50.0 mL) was added. The reaction mixture was extracted with EA (100 mL x 3). The combined organic phases were washed with brine (100.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA = 10/1) to give N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide (267 mg, 90% purity) as a brown solid. LCMS (M+H ⁺ ) m/z: 411.0.

[0739] Step 3: Synthesis of N-(4-fluoro-3-(5-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0740] 1,4-디옥산 (3 mL) 및 H ₂ O (0.2 mL) 중 6-브로모-N,5-디메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (30 mg, 0.1 mmol, 1.0 equiv), N-(4-플루오로-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린아미드 (41 mg, 0.1 mmol, 1.0 equiv), Cs ₂ CO ₃ (100 mg, 0.3 mmol, 3.0 equiv), 및 PdCl ₂ (dppf) (15 mg, 0.02 mmol, 20 mol %)의 혼합물을 120℃에서 40분 동안 MW 하에 교반하였다. The reaction mixture was purified by flash (DCM: MeOH=10:1) to give 15 mg crude product which was further purified by HPLC to obtain pure product N-(4-fluoro-3-(5-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (8.9 mg) was obtained as a yellow solid. ^1H NMR (400 MHz, CD ₃ OD): δ 8.96 (d, J = 4.8 Hz, 1H), 8.87 (s, 1H), 8.52 (s, 1H), 8.42 (s, 1H), 7.96-7.92 (m, 3H), 7.36 (t, J = 9.6 Hz, 1H), 4 .65-4.62 (m, 2H), 4.07-4.03 (m, 2H), 3.05 (s, 3H), 2.36 (s, 3H). LCMS (M+H ⁺ ) m/z: 498.0.

Example 122: N-(4-methyl-3-(4-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 122) manufacturing

[0741] Step 1: Synthesis of 4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0742] To a solution of 4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (500 mg, 2.41 mmol) in DCM (10 mL) was added m-CPBA (1.04 g, 6 mmol) and the reaction mixture was stirred at room temperature for 2 hours. LCMC results indicated that the reaction was complete. The reaction mixture was concentrated to give a yellow solid. The crude solid was diluted with THF (12 mL, 24 mmol) in THF (5 mL). 2M methylamine in The mixture was stirred at 60° C. for 2 hours. LCMC results indicated that the reaction was complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were dried over brine (20 mL), anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by prep-HPLC to give 4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (400 mg, 72% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 191.1.

[0743] Step 2: Synthesis of 6-bromo-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0744] To a solution of 4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (400 mg, 2.1 mmol) in DMF (6 mL) was added NBS (409 mg, 2.3 mmol). The mixture was stirred at 25° C. for 2 hours. LCMC results indicated that the reaction was complete. The reaction mixture was diluted with water (20 mL). The resulting red precipitated solid was filtered and the cake was diluted with water (10 mL). The solid was dried to give 6-bromo-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (450 mg, 80% yield) as a red solid. LCMS (M+H+) m/z: 269.0.

[0745] Step 3: Synthesis of 6-bromo-7-chloro-N,4-dimethylpyrido[2,3-d]pyrimidin-2-amine

[0746] A mixture of 6-bromo-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (450 mg, 1.67 mmol) in POCl ₃ (5 mL) was stirred at 110 °C for 2 h. LCMC results indicated that the reaction was complete. The reaction mixture was concentrated to give a crude oil which was diluted with saturated aqueous NaHCO ₃ solution (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give crude 6-bromo-7-chloro-N,4-dimethylpyrido[2,3-d]pyrimidin-2-amine (450 mg, crude) which was used in the next step without further purification. LCMS (M+H+) m/z: 286.9.

[0747] Step 4: Synthesis of 2-((6-bromo-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol

[0748] To a mixture of 6-bromo-7-chloro-N,4-dimethylpyrido[2,3-d]pyrimidin-2-amine (450 mg, 1.56 mmol) in EtOH (2 mL) was added 2-aminoethane-1-ol (571 mg, 9.36 mmol). The mixture was stirred at 80° C. for 16 hours. LCMC results indicated that the reaction was complete. The reaction mixture was concentrated, diluted with water (10 mL), and extracted with DCM/MeOH=10:1 (10 mL*5). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 2-((6-bromo-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (310 mg, crude) which was used in the next step without further purification. LCMS (M+H+) m/z: 311.9.

[0749] Step 5: Synthesis of 6-bromo-N,4-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0750] A mixture of 2-((6-bromo-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (310 mg, 1 mmol) in THF (5 mL) was added to MsCl (229 mg, 2 mmol). The mixture was stirred at 25 °C for 3 hours. LCMC results indicated that the reaction was complete. The reaction mixture was diluted with water (5 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography to give 6-bromo-N,4-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (210 mg, 72% yield). LCMS (M+H+) m/z: 294.0.

[0751] Step 6: Synthesis of N-(4-methyl-3-(4-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0752] N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phenyl)-4-(trifluoromethyl)picolinamide (55 mg, 0.14 mmol), Pd(dppf)Cl ₂ (10 mg, 0.014 mmol) and K ₂ CO ₃ (39 mg, 0.28 mmol) were added. The mixture was bubbled under nitrogen for 5 minutes and then stirred at 90° C. for 2 hours. LCMC results indicated that the reaction was complete. The reaction mixture was filtered through celite, and the filtrate was diluted with water (5 mL) and extracted with EA (5 mL*3). The combined organic phases were washed with brine (10 mL) and dried over anhydrous Na2SO4 to give a crude oil. The crude oil was purified by prep-HPLC to give N-(4-methyl-3-(4-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (8.4 mg) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.75 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 8.09 (d, J = 4.4 Hz, 1H), 7.81 (d, J = 4.8 Hz, 2H), 7.47-7.36 (m, 2H), 7.24 (d, J = 8.8 Hz, 1H), 4.12-4.00 (m, 2H), 3.90 (t, J = 9.6 Hz, 2H), 2.85 (d, J = 4.8 Hz, 3H), 2.37 (s, 3H), 2.21 (s, 3H). LCMS (M+H ⁺ ) m/z: 494.0.

Example 123: N-(4-chloro-3-(4-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 123) manufacturing

[0753] Step 1: Synthesis of N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl) picolinamide

[0754] 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.54 g, 10.0 mmol), Pd(dppf) Cl ₂ (365 mg, 0.50 mmol), KOAc (1.47 g, 15 mmol) were added. The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was filtered through celite. The filtrate was concentrated under vacuum. The residue was triturated with PE and filtered to give N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl) picolinamide (1.2 g, crude) as a gray solid. LCMS (M+H ⁺ ) m/z: 427.0.

[0755] Step 2: Synthesis of N-(4-chloro-3-(4-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0756] N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phenyl)-4-(trifluoromethyl)picolinamide (58 mg, 0.14 mmol), Pd(dppf)Cl ₂ (10 mg, 0.014 mmol) and K ₂ CO ₃ (39 mg, 0.28 mmol) were added. The mixture was bubbled with nitrogen for 5 minutes and then stirred at 90° C. for 2 hours. LCMC results indicated that the reaction was complete. The reaction mixture was filtered through celite, and the filtrate was diluted with water (5 mL) and extracted with EA (5 mL*3). The combined organic phases were washed with brine (10 mL) and dried over anhydrous Na ₂ SO ₄ to give a crude oil. The crude oil was purified by prep-HPLC to give N-(4-chloro-3-(4-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (14 mg) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.00 (s, 1H), 9.04 (d, J = 5.2 Hz, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 8.11 (d, J = 4.0 Hz, 1H), 8.06 (s, 1H), 7.95 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.56-7.46 (m, 3H), 4.14-3.93 (m, 2H), 3.90 (t, J = 9.6 Hz, 2H), 2.85 (d, J = 4.8 Hz, 3H), 2.37 (s, 3H). LCMS (M+H ⁺ ) m/z: 514.0.

Example 124 N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[2,1-h]pteridine -6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 124) manufacturing

[0757] Step 1: Synthesis of ethyl 2-((4-amino-2-chloropyrimidin-5-yl)imino)acetate

[0758] To a solution of 2-chloropyrimidine-4,5-diamine (2.88 g, 20 mmol) in EtOH (30 mL) was added ethyl 2-oxoacetate (50% w/w% in toluene) (4.08 g, 20 mmol) and AcOH (2 drops) were added and the reaction mixture was stirred at 100 °C for 2 h. LCMC results indicated that the reaction was complete. The reaction mixture was filtered to give a yellow solid. The crude solid was dried under vacuum to give ethyl 2-((4-amino-2-chloropyrimidin-5-yl)imino)acetate (2.1 g) as a yellow solid. LCMS (M+H ⁺ ) m/z: 228.9.

[0759] Step 2: Synthesis of 2-chloropteridin-7(8H)-one

[0760] To a solution of ethyl 2-((4-amino-2-chloropyrimidin-5-yl)imino)acetate (2.1 g, 9.2 mmol) in THF (20 mL) was added NaOMe (993 mg, 18.4 mmol). The mixture was stirred at 25 °C for 1 hour. LCMC results indicated that the reaction was complete. The reaction mixture was diluted with water (20 mL), the precipitate obtained was filtered and the cake was washed with water (10 mL). The solid was dried to give 2-chloropteridin-7(8H)-one (830 mg, 50% yield) as a red solid. LCMS (M+H+) m/z: 183.0.

[0761] Step 3: Synthesis of 2-(methylamino)pteridin-7(8H)-one

[0762] To a mixture of 2-chloropteridin-7(8H)-one (830 mg, 4.6 mmol) in EtOH (5 mL) was added methylamine (33% in EtOH) (5 mL) and the reaction mixture was stirred at 50 °C for 6 h. LCMC results indicated that the reaction was complete. The reaction mixture was concentrated to give 2-(methylamino)pteridin-7(8H)-one (650 mg, crude), which was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 178.0.

[0763] Step 4: Synthesis of 7-chloro-N-methylpteridin-2-amine

[0764] A mixture of 2-(methylamino)pteridin-7(8H)-one (400 mg, 2.26 mmol) in POCl ₃ (5 mL) was stirred at 110 °C for 3 h. LCMC results indicated that the reaction was complete. The reaction mixture was concentrated to give a crude oil which was diluted with saturated aqueous NaHCO3 solution (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give 7-chloro-N-methylpteridin-2-amine (600 mg, crude). This crude solid was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 196.1.

[0765] Step 5: Synthesis of 2-((2-(methylamino)pteridin-7-yl)amino)ethan-1-ol

[0766] A mixture of 7-chloro-N-methylpteridin-2-amine (600 mg, crude) in EtOH (6 mL) was added to 2-aminoethane-1-ol (1.22 g, 20 mmol). The mixture was stirred at 80 °C for 3 hours. LCMC results indicated that the reaction was complete. The reaction mixture was concentrated, diluted with water (10 mL) and extracted with DCM/MeOH=10:1 (10 mL*5). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product which was purified by pre-HPLC to give 2-((2-(methylamino)pteridin-7-yl)amino)ethan-1-ol (300 mg) as a white solid. LCMS (M+H+) m/z: 221.1.

[0767] Step 6: Synthesis of 2-((6-bromo-2-(methylamino)pteridin-7-yl)amino)ethan-1-ol

[0768] To a mixture of 2-((2-(methylamino)pteridin-7-yl)amino)ethan-1-ol (220 mg, 1 mmol) in DMF (5 mL) was added NBS (356 mg, 2 mmol). The mixture was stirred at 25 °C for 5 hours. LCMC results indicated that the reaction was complete. The reaction mixture was diluted with water (5 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography to give 2-((6-bromo-2-(methylamino)pteridin-7-yl)amino)ethan-1-ol (150 mg, 50% yield). LCMS (M+H+) m/z: 299.0.

[0769] Step 7: Synthesis of 6-bromo-N-methyl-8,9-dihydroimidazo[2,1-h]pteridin-2-amine

[0770] To a mixture of 2-((6-bromo-2-(methylamino)pteridin-7-yl)amino)ethan-1-ol (150 mg, 0.5 mmol) in DCM (3 mL) was added DIEA (129 mg, 1 mmol) and MsCl (115 mg, 1 mmol). The mixture was stirred at 25 °C for 4 hours. LCMC results indicated that the reaction was complete. The reaction mixture was diluted with water (5 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography to obtain 6-bromo-N-methyl-8,9-dihydroimidazo[2,1-h]pteridin-2-amine (80 mg, 57% yield). LCMS (M+H+) m/z: 281.0.

[0771] Step 8: Synthesis of N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[2,1-h]pteridin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0772] N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl) Picolinamide (57 mg, 0.14 mmol), Pd(dppf)Cl ₂ (10 mg, 0.014 mmol) and K ₂ CO ₃ (39 mg, 0.28 mmol) were added. The mixture was bubbled with nitrogen for 5 minutes and then stirred at 90° C. for 2 hours. LCMC results indicated that the reaction was complete. The reaction mixture was filtered through celite and the filtrate was diluted with water (5 mL) and extracted with EA (5 mL*3). The combined organic phases were washed with brine (10 mL) and dried over anhydrous Na ₂ SO ₄ to give a crude oil. This crude oil was purified by prep-HPLC to give N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[2,1-h]pteridin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (3.1 mg) as a yellow solid. ¹ H NMR (400 MHz, CD3OD): δ 8.86 (d, J = 5.0 Hz, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 7.83 (dd, J = 9.6, 3.2 Hz, 2H), 7.74 (dd, J = 8.4, 2.4 Hz, 1H), 7.2 5 (d, J = 8.4 Hz, 1H), 4.16 (br s, 2H), 4.01 (t, J = 9.6 Hz, 2H), 2.90 (s, 3H), 2.24 (s, 3H). LCMS (M+H ⁺ ) m/z: 481.1.

Example 125: N-(4-methyl-3-(8-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 125) manufacturing

[0773] Step 1: Synthesis of 2-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)propan-1-ol

[0774] A mixture of 6-bromo-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (1.0 g, 3.45 mmol) and 2-aminopropan-1-ol (517 mg, 6.89 mmol) in iPrOH (15.0 mL) was stirred at reflux for 3.0 h. The reaction mixture was concentrated. Water was added and the precipitate was filtered to give 2-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)propan-1-ol (1.11 g, 98% yield) as an off-white solid. LCMS (M+H+) m/z: 329.0 and 331.0.

[0775] Step 2: Synthesis of 6-bromo-8-methyl-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0776] To a mixture of 2-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)propan-1-ol (1.16 g, 3.5 mmol), TEA (1.06 g, 10.5 mmol) in DCM (20.0 mL) was added MsCl (1.0 g, 8.8 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, diluted with cold water (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA=3/1) to give 6-bromo-8-methyl-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (1.0 g, 91% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 311.0 and 313.0.

[0777] Step 3: Synthesis of 6-bromo-8-methyl-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0778] To a solution of 6-bromo-8-methyl-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (250 mg, 0.8 mmol) in dry DCM (20 mL) was added m-CPBA (368 mg, 1.6 mmol) at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was concentrated under vacuum at room temperature to afford crude 6-bromo-8-methyl-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (250 mg, crude) as a yellow solid which was used in the next step without further purification. LCMS (M+H) ⁺ m/z: 326.9 and 328.9.

[0779] Step 4: Synthesis of 6-bromo-N,8-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0780] To a solution of crude 6-bromo-8-methyl-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (250 mg, 0.76 mmol) in THF (20.0 mL) was added MeNH ₂ (2 M in THF, 1.5 mL, 3.0 mmol). The mixture was stirred at room temperature for 16 hours and concentrated. Water (80 mL) was added and the reaction mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was added to EA (4.0 mL), stirred at room temperature for 3.0 hours and filtered to give 6-bromo-N,8-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (200 mg, 88% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 294.0 and 296.0.

[0781] Step 5: Synthesis of N-(4-methyl-3-(8-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0782] 디옥산 (15.0 mL) 및 물 (3 mL) 중 6-브로모-N,8-디메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (200 mg, 0.68 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린아미드 (276 mg, 0.68 mmol), Cs ₂ CO ₃ (665 mg, 2.04 mmol) 및 Pd(dppf)Cl ₂ (75 mg, 0.102 mmol)의 혼합물을 탈기하고 N ₂ 를 3회 충전하고 100℃에서 16 시간 교반하였다. The reaction mixture was diluted with water (80 mL) and extracted with EA (50 mL*3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% HCOOH) to afford N-(4-methyl-3-(8-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (119.4 mg, 35% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.75 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 8.08-8.09 (m, 1H), 7.81 (d, J = 2.0 Hz, 2H), 7.78 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.38-7.43 (m, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 4.21-4.24 (m, 2H), 3.52-3.63 (m, 1H), 2.85 (d, J = 4.4 Hz, 3H), 2.21 (s, 3H), 1.20 (d, J = 6.4 Hz, 3H). LCMS (M+H ⁺ ) m/z: 494.4.

Example 126 and 127: (S)-N-(4-methyl-3-(8-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (Compound 126) and (R)-N-(4-methyl-3-(8-methyl-2-(methylamino) -8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 127) manufacturing

[0783] Compound 125 (60 mg) was separated by Chiral-HPLC to give Compound 126 (12.9 mg) and Compound 127 (12.5 mg). 화합물 126： ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.76 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.33 (s, 1H), 8.28-8.22 (m, 1H), 8.08 (d, J = 4.4 Hz, 1H), 7.82 (s, 1H), 7.80-7.77 (m, 1H), 7.53-7.41 (m, 1H), 7.25-7.21 (m, 1H), 4.25 (s, 2H), 3.66 (s, 1H), 2.86 (s, 3H), 2.21 (s, 3H), 1.22-1.21 (m, 3H). LCMS (M+H ⁺ ) m/z: 494.4. 화합물 127： ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.76 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 8.09-8.08 (m, 1H), 7.82-7.81 (m, 1H), 7.79-7.77 (m, 1H), 7.49-7.41 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 4.24 (s, 2H), 3.63 (s, 1H), 2.86 (d, J = 3.2 Hz, 3H), 2.21 (s, 3H), 1.22-1.20 (m, 3H). LCMS (M+H ⁺ ) m/z: 494.4.

Example 128: N-(4-methyl-3-(9-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 128) manufacturing

[0784] Step 1: Synthesis of 1-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)propan-2-ol

[0785] A mixture of 6-bromo-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (1.0 g, 3.45 mmol) and 1-aminopropan-2-ol (517 mg, 6.89 mmol) in iPrOH (15.0 mL) was stirred at reflux for 3 hours. The reaction mixture was concentrated and diluted with water (20 mL). The resulting solid was filtered to give 1-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)propan-2-ol (1.16 g, 100% yield) as an off-white solid. LCMS (M+H ⁺ ) m/z: 329.0 and 331.0.

[0786] Step 2: Synthesis of 6-bromo-9-methyl-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0787] To a mixture of 1-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)propan-2-ol (1.07 g, 3.27 mmol), TEA (1.98 g, 19.62 mmol) in DCM (20.0 mL) was added MsCl (1.49 g, 13.08 mmol). The resulting mixture was stirred at 35°C for 16 hours. The reaction mixture was concentrated, diluted with cold water (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA=3/1) to give 6-bromo-9-methyl-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (776 mg, 75% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 311.0 and 313.0.

[0788] Step 3: Synthesis of 6-bromo-9-methyl-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[0789] To a solution of 6-bromo-9-methyl-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (200 mg, 0.64 mmol) in dry DCM (8.0 mL) was added m-CPBA (294 mg, 1.28 mmol) at 0 °C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was concentrated to give crude 6-bromo-9-methyl-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (500 mg, 100% yield) as a yellow solid, which was used in the next step without further purification. LCMS (M+H2O) ⁺ m/z: 326.9 and 328.9.

[0790] Step 4: Synthesis of 6-bromo-N,9-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0791] To a solution of crude 6-bromo-9-methyl-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (500 mg, 1.5 mmol) in THF (10.0 mL) was added MeNH ₂ (2 M in THF, 3.0 mL, 3.0 mmol). The mixture was stirred at room temperature for 16 hours and concentrated. Water was added and the mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was added to EA (4.0 mL), stirred at room temperature for 3.0 hours and filtered to give 6-bromo-N,9-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (230 mg, 51% yield) as a yellow solid. LCMS (M+H+) m/z: 293.9 and 295.9.

[0792] Step 5: N-(4-methyl-3-(9-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0793] 디옥산 (15.0 mL) 및 물 (3 mL) 중 6-브로모-N,9-디메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (230 mg, 0.78 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린아미드 (276 mg, 0.78 mmol), Cs ₂ CO ₃ (760 mg, 2.34 mmol) 및 Pd(dppf)Cl ₂ (57 mg, 0.078 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 변경하고 100℃에서 16 시간 교반하였다. The reaction mixture was diluted with water (80.0 mL) and extracted with EA (50 mL*3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% HCOOH) to afford N-(4-methyl-3-(9-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (113.1 mg, 29% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.75 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 8.09-8.08 (m, 1H), 7.82 (d, J = 2.0 Hz, 2H), 7.79 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.52-7.40 (m, 1H), 7.25-7.17 (m, 1H), 4.74-4.63 (m, 1H), 4.05 (t, J = 14.4 Hz, 1H), 3.50 (dd, J = 15.2, 4.8 Hz, 1H), 2.85 (d, J = 4.0 Hz, 3H), 2.20 (s, 3H), 1.48 (s, 3H). LCMS (M+H ⁺ ) m/z: 494.3.

Example 129 and 130: (R)-N-(4-methyl-3-(9-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (Compound 129) and (S)-N-(4-methyl-3-(9-methyl-2-(methylamino) -8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 130) manufacturing

[0794] N-(4-methyl-3-(9-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (60 mg) was isolated by chiral-HPLC to obtain (R)-N-(4-methyl-3-(9-methyl-2-(methylamino)-8, 9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (Compound 129) (21 mg) and (S)-N-(4-methyl-3-(9-methyl-2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyridonium Midin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (Compound 130) (16 mg) was obtained as a yellow solid. 화합물 129： ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.74 (s, 1H), 9.025 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 8.09-8.08 (m, 1H), 7.81 (s, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.23 (d, J = 4.4 Hz, 1H), 4.67 (s, 1H) , 4.06-4.01 (m, 2H), 3.94-3.89 (m, 2H), 2.20 (s, 3H), 1.45-1.23 (m, 3H). LCMS (M+H ⁺ ) m/z: 494.4. 화합물 130： ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.74 (s, 1H), 9.03 (m, 1H), 8.34 (s, 1H), 8.23 (s, 1H), 8.09-8.08 (m, 1H), 7.81-7.78 (m, 2H), 7.41 (m, 1H), 7.41-7.35 (m, 1H), 7.23-7.21 (m, 1H), 7.11 (s, 1H), 4.68 (s, 1H), 4.08-4.02 (m, 1H), 3.51-3.48 (m, 1H), 2.20 (s, 3H), 1.46 (s, 3H). LCMS (M+H ⁺ ) m/z: 494.4.

Example 131: N-(4-methyl-3-(2'-(methylamino)-8'H-spiro[cyclopentane-1,9'-imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin]-6'-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 131) manufacturing

[0795] Step 1: Synthesis of 1-(((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)methyl)cyclopentan-1-ol

[0796] A mixture of 6-bromo-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (1.43 g, 4.92 mmol) and 1-(aminomethyl)cyclopentan-1-ol (0.85 g, 7.38 mmol) in TEA (40.0 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated, diluted with water (100.0 mL) and extracted with DCM (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA=1/1) to give 1-(((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)methyl)cyclopentan-1-ol (1.79 g, 98% yield) as an off-white solid. LCMS (M+H+) m/z: 368.8 and 370.8.

[0797] Step 2: Synthesis of 6'-Bromo-2'-(methylthio)-8'H-spiro[cyclopentane-1,9'-imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine]

[0798] To a mixture of 1-(((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)methyl)cyclopentan-1-ol (500 mg, 1.35 mmol), N,N-dimethylaniline (164 mg, 1.35 mmol) in ACN (40.0 mL) was added POCl ₃ (1.66 g, 10.84 mmol). added. The resulting mixture was stirred at 85°C for 16 hours. The reaction mixture was concentrated, diluted with cold water (50.0 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA=3/1) to give 6'-bromo-2'-(methylthio)-8'H-spiro[cyclopentane-1,9'-imidazo[1',2':1,6]pyrido[2,3-d] pyrimidine] (255 mg, 47% yield) as a yellow solid. LCMS (M+H+) m/z: 351.0 and 353.0.

[0799] Step 3: Synthesis of 6'-Bromo-2'-(methylsulfinyl)-8'H-spiro[cyclopentane-1,9'-imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine]

[0800] To a solution of 6'-bromo-2'-(methylthio)-8'H-spiro[cyclopentane-1,9'-imidazo[1',2':1,6]pyrido[2,3-d] pyrimidine] (175 mg, 0.5 mmol) in dry DCM (5.0 mL) was added m-CPBA (229 mg, 1.0 mmol) at 0 °C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was concentrated to give crude 6'-bromo-2'-(methylsulfinyl)-8'H-spiro[cyclopentane-1,9'-imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine] (400 mg, crude) as a yellow solid which was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 366.9 and 368.9.

[0801] Step 4: Synthesis of 6'-bromo-N-methyl-8'H-spiro[cyclopentane-1,9'-imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine]-2'-amine

[0802] To a solution of crude 6'-bromo-2'-(methylsulfinyl)-8'H-spiro[cyclopentane-1,9'-imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine] (400 mg, 0.50 mmol) in THF (5.0 mL) was added MeNH ₂ (2 M in THF, 1.5 mL, 3.0 mmol). added. The mixture was stirred at room temperature for 1.5 hours and concentrated. Water was added and the mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), Na ₂ SO ₄ , filtered and concentrated. The residue was added to EA (4.0 mL), stirred at room temperature for 3 hours, filtered to give 6'-bromo-N-methyl-8'H-spiro[cyclopentane-1,9'-imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin]-2'-amine (134 mg, 63% yield) as a pale yellow solid. LCMS (M+H+) m/z: 334.0 and 336.0.

[0803] Step 5: Synthesis of N-(4-methyl-3-(2'-(methylamino)-8'H-spiro[cyclopentane-1,9'-imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin]-6'-yl)phenyl)-4-(trifluoromethyl)picolinamide hydrogen chloride

[0804] 디옥산 (8.0 mL) 및 물 (0.8 mL) 중 6'-브로모-N-메틸-8'H-스피로[시클로펜탄-1,9'-이미다조[1',2':1,6]피리도[2,3-d] 피리미딘]-2'-아민 (134 mg, 0.4 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-4-(트리플루오로메틸)피콜린아미드 (195 mg, 0.48 mmol), Cs ₂ CO ₃ (392 mg, 1.2 mmol) 및 Pd(dppf)Cl ₂ (29 mg, 0.04 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전한 다음 100℃에서 4 시간 교반하였다. The reaction mixture was diluted with water (80.0 mL) and extracted with EA (50 mL*3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% HCl) to afford N-(4-methyl-3-(2'-(methylamino)-8'H-spiro[cyclopentane-1,9'-imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin]-6'-yl)phenyl)-4-(trifluoromethyl)picolinamide hydrogen chloride (39.6 mg, 17% yield) as yellow Obtained as a solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.89 (s, 1H), 9.89-9.38 (m, 1H), 9.05 (d, J = 4.4 Hz, 1H), 8.98-8.90 (m, 2H), 8.55 (s, 1H), 8.34 (s, 1H), 8.13 (d, J = 7.6 Hz, 2H), 8.01 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 3.93 (s, 2H), 3.04-2.94 (m, 5H), 2.21 (s, 3H), 2.03-1.97 (m, 4H), 1.73 (s, 2H). LCMS (M+H ⁺ ) m/z: 534.4.

Example 132 N-(4- methyl -3-(8-( methylamino )-1,2- dihydroimidazo [1,2-a][1,6] naphthyridine -4-yl) phenyl) -4- ( trifluoromethyl ) picolinamide (Compound 132)

[0805] Step 1: Synthesis of 3-bromo-7-chloro-1,6-naphthyridin-2(1H)-one

[0806] A mixture of 7-chloro-1,6-naphthyridin-2(1H)-one (400 mg, 2.21 mmol) in AcOH (6 mL) and TFA (4 mL) was stirred at room temperature for 20 minutes. NBS (439 mg, 2.44 mmol) was added and the mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with saturated NaHCO ₃ solution (100 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give 3-bromo-7-chloro-1,6-naphthyridin-2(1H)-one (500 mg, crude) as a yellow solid. LCMS (M+H ⁺ ) m/z: 260.8.

[0807] Step 2: Synthesis of 3-bromo-7-(methylamino)-1,6-naphthyridin-2(1H)-one

[0808] To a mixture of 3-bromo-7-chloro-1,6-naphthyridin-2(1H)-one (700 mg, 2.70 mmol) in THF (10 mL) was added methylamine (15 mL, 2 M in THF) was added. The solution was stirred at 140 °C for 24 hours. The reaction mixture was concentrated and the residue was purified by prep-HPLC (0.1% NH3.H2O) to give 3-bromo-7-(methylamino)-1,6-naphthyridin-2(1H)-one (250 mg, 36% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 254.0.

[0809] Step 3: Synthesis of 3-bromo-2-chloro-N-methyl-1,6-naphthyridin-7-amine

[0810] A mixture of 3-bromo-7-(methylamino)-1,6-naphthyridin-2(1H)-one (180 mg, 0.71 mmol) in POCl ₃ (10 mL) was stirred at 95 °C for 16 h. The reaction mixture was concentrated then saturated NaHCO ₃ (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give 3-bromo-2-chloro-N-methyl-1,6-naphthyridin-7-amine (250 mg, crude) as a yellow oil. LCMS (M+H ⁺ ) m/z: 274.1.

[0811] Step 4: Synthesis of 2-((3-bromo-7-(methylamino)-1,6-naphthyridin-2-yl)amino)ethan-1-ol

[0812] A mixture of 3-bromo-2-chloro-N-methyl-1,6-naphthyridin-7-amine (250 mg, 0.90 mmol) 2-aminoethane-1-ol (84 mg, 1.4 mmol) in iPrOH (5 mL) was stirred at 90 °C for 16 h. The reaction mixture was concentrated and purified by silica column chromatography (EA:PE = 5% to 80%) to give 2-((3-bromo-7-(methylamino)-1,6-naphthyridin-2-yl)amino)ethan-1-ol (60 mg, 22% yield) as a yellow oil. LCMS (M+H ⁺ ) m/z: 299.0.

[0813] Step 5: Synthesis of 4-bromo-N-methyl-1,2-dihydroimidazo[1,2-a][1,6]naphthyridin-8-amine

[0814] SOCl ₂ (120 mg, 1.0 mmol) was added to a solution of 2-((3-bromo-7-(methylamino)-1,6-naphthyridin-2-yl)amino)ethan-1-ol (60 mg, 0.20 mmol) in CHCl ₃ (3 mL). The reaction mixture was stirred at 70 °C for 6 hours. The mixture was quenched with saturated NaHCO ₃ (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (100 mL) and dried over Na ₂ SO ₄ , filtered and concentrated to give the crude which was purified by silica column chromatography (EA/PE=5% to 80%) to give 4-bromo-N-methyl-1,2-dihydroimidazo[1,2-a][1,6]naphthyridin-8-amine (20 mg, 36% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 279.1

[0815] Step 6: Synthesis of N-(4-methyl-3-(8-(methylamino)-1,2-dihydroimidazo[1,2-a][1,6]naphthyridin-4-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0816] 디옥산:H ₂ O (10:1) (2 mL) 중 4-브로모-N-메틸-1,2-디히드로이미다조[1,2-a][1,6]나프티리딘-8-아민 (15 mg, 0.05 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸) 피콜린아미드 (32.7 mg, 0.08 mmol), Cs ₂ CO ₃ (52 mg, 0.16 mmol) 및 Pd(dppf)Cl ₂ (3.9 mg, 0.005 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전한 다음, 110℃에서 16 시간 교반하였다. The reaction mixture was concentrated, diluted with 3M HCl (30 mL) and extracted with DCM (30 mL). NH _3. The aqueous phase was adjusted to pH=10 with H ₂ O and extracted with DCM (30 mL x3). The combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product which was purified by preparative-TLC (DCM: MeOH=10:1) then preparative-HPLC (0.1% NH ₃ H ₂ O) to obtain N-(4-methyl-3-(8-(methylamino)-1,2-dihydroimidazo[1,2-a][1,6] or Obtained phthalidin-4-yl)phenyl)-4-(trifluoromethyl)picolinamide (3.4 mg, 10% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ): δ 8.96-8.95 (m, 1 H), 8.42 (d, J=8.8 Hz, 2 H), 7.92 (d, J=5.2 Hz, 1 H), 7.84-7.83 (m, 1 H), 7.80-7.76 (m, 2 H), 7 .39 (d, J=8.4 Hz, 1 H), 6.10 (s, 1 H), 4.45 (t, J=10.4 Hz, 2 H), 4.08 (t, J=10.4 Hz, 2 H), 2.99 (s, 3 H), 2.27 (s, 3 H). LCMS (M+H+) m/z: 479.2.

Example 133: N-(2-chloro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 133) manufacturing

[0817] The preparation of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidine is described in Example 109.

[0818] Step 1: Synthesis of 6-bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0819] To a mixture of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (1.2 g, 3.85 mmol) in THF (20 mL) was added MeNH ₂ (2.0 M in THF, 5.8 mL, 11.55 mmol) at room temperature. The reaction mixture was stirred 1 hour at RT. The reaction mixture was dried in vacuo to afford 6-bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (710 mg, 75.4% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 280.0 and 282.0.

[0820] Step 2: Synthesis of 4-bromo-5-methyl-2-nitroaniline

[0821] To a solution of 5-methyl-2-nitroaniline (3.0 g, 19.7 mmol) in AcOH (100 mL) was added NBS (3.58 g, 20.1 mmol). The mixture was stirred at 120° C. under N2 for 1.5 h. The mixture was poured into water (300 mL) and filtered to give 4-bromo-5-methyl-2-nitroaniline (4.2 g, 93% yield) as a yellow solid.

[0822] Step 3: Synthesis of 1-bromo-4-chloro-2-methyl-5-nitrobenzene

[0823] 4-Bromo-5-methyl-2-nitroaniline (2.0 g, 8.66 mmol) in AcOH (20 mL) was added slowly to a solution of NaNO ₂ (955 mg, 13.8 mmol) in concentrated H ₂ SO ₄ (10 mL) while maintaining the temperature below 40 °C. The mixture was stirred at room temperature for 30 minutes. The resulting mixture was slowly added to a solution of CuCl (2.0 g, 20.7 mmol) in concentrated HCl (25 mL). The reaction mixture was stirred at 60° C. for 2 hours. Water was added and the resulting precipitate was filtered to give 1-bromo-4-chloro-2-methyl-5-nitrobenzene (1.5 g, 70% yield) as a gray solid.

[0824] Step 4: Synthesis of 5-bromo-2-chloro-4-methylaniline

[0825] To a solution of 1-bromo-4-chloro-2-methyl-5-nitrobenzene (800 g, 3.19 mmol) in EtOH (8 mL) and HO (2 mL) was added Fe powder (894 mg, 15.9 mmol) and concentrated HCl (0.5 mL). The mixture was stirred at 80° C. for 16 hours. The mixture was filtered, concentrated and purified by silica gel column chromatography (PE : EA = 4 : 1) to give 5-bromo-2-chloro-4-methylaniline (550 mg, 78% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 219.9.

[0826] Step 5: Synthesis of N-(5-bromo-2-chloro-4-methylphenyl)-4-(trifluoromethyl)picolinamide

[0827] To a solution of 5-bromo-2-chloro-4-methylaniline (420 mg, 1.90 mmol) in DCM (10 mL) was added 4-(trifluoromethyl)picolinic acid (436 mg, 2.28 mmol), T3P (1.2 g, 3.81 mmol) and TEA (578 mg, 5.72 mmol). The mixture was stirred at room temperature under N2 for 2 hours. The mixture was diluted with water (30 mL) then extracted with DCM (30 mL x 3). The residue was purified by silica gel column chromatography (PE : EA = 10 : 1) to give N-(5-bromo-2-chloro-4-methylphenyl)-4-(trifluoromethyl)picolinamide (550 mg, 73% yield) as a white solid. LCMS (M+H+) m/z: 395.0.

[0828] Step 6: Synthesis of N-(2-chloro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0829] 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (193 mg, 0.76 mmol) , Pd(dppf)Cl2 (27 mg, 0.038 mmol) and AcOK (112 mg, 1.14 mmol) were added. The mixture was stirred at 110° C. under N2 for 16 hours. The mixture was concentrated and purified by silica gel column chromatography (PE : EA = 10 : 1) to give N-(2-chloro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide (110 mg, 66% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 441.1.

[0830] Step 7: Synthesis of N-(2-chloro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0831] 6-Bromo-N-methyl-8,9-dihydroimida in a solution of N-(2-chloro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide (110 mg, 0.25 mmol) in 1,4-dioxane (5 mL) and HO (0.5 mL) Crude[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (77 mg, 0.27 mmol), Pd(dppf)Cl2 (18 mg, 0.025 mmol) and Cs2CO3 (224 mg, 0.75 mmol) were added. The mixture was stirred at 110° C. under N2 for 16 hours. The mixture was purified by preparative-HPLC (0.1%/HCl/CHCN/HO) to afford N-(2-chloro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (7.4 mg, 6% yield) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.65 (s, 1H), 9.92 (s, 1H), 9.83 (s, 1H), 9.09 (d, J = 5.2 Hz, 1H), 8.98 (s, 1H), 8.89 (s, 1H), 8.56 (q, J = 4.8 Hz, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 8.19 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 7.70 (s,1H), 4.67-4.53 (m, 2H), 4.06-3.98 (m, 2H), 2.97 (d, J = 4.8 Hz, 3H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 514.0.

Example 134 N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide (compound 134) manufacturing

[0832] Step 1: Synthesis of 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0833] To a solution of 6-bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (600 mg, 2.14 mmol) in dioxane (12 mL) and HO (1 mL) was added 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxabo Rolan-2-yl)aniline (591 mg, 2.35 mmol), Pd(dppf)Cl ₂ (156 mg, 0.21 mmol) and Cs ₂ CO ₃ (2.0 g, 6.42 mmol) was added. The mixture was stirred at 110° C. under N ₂ for 16 h. The mixture was concentrated and purified by column chromatography (DCM:MeOH=10:1) to give 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (320 mg, 46%, 0.99 mmol) as a gray solid. LCMS (M+H ⁺ ) m/z: 325.2.

[0834] Step 2: Synthesis of N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide

[0835] 2-(3-(trifluoromethyl)phenyl)acetic acid (27 mg, 0.13 mmol), HATU (7 0 mg, 0.18 mmol) and TEA (37 mg, 0.37 mmol) were added. The mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative-HPLC (0.1%/HCl/CH3CN/H2O) to N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide (28.3 mg, 46% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.27 (s, 1H), 9.70 (s, 1H), 8.84 (s, 1H), 8.52 (q, J = 4.8 Hz, 1H), 8.06 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.65-7.55 (m, 3H), 7.33 (d, J = 12.0 Hz, 1H), 4.64-4.51 (m, 2H), 4.01-3.96 (m, 2H), 3.89 (s, 2H), 2.95 (d, J = 4.8 Hz, 3H), 2.16 (s, 3H). LCMS (M+H ⁺ ) m/z: 511.4.

Example 135: N-(4-fluoro-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 135) manufacturing

[0836] Preparation of 6-bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine and N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide 133 is described.

[0837] Step 1: Synthesis of N-(4-fluoro-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

6-Bromo _- N-methyl-8,9-dihydroimidazo[1',2' :1,6]pyrido[2,3-d]pyrimidin-2-amine (165 mg, 0.59 mmol), Pd(dppf)Cl ₂ (44 mg, 0.06 mmol), Cs ₂ CO ₃ (577 mg, 1.77 mmol) were added and the mixture was degassed 3 times then charged with N ₂ and stirred at 100° C. for 3 h. The reaction mixture was concentrated in vacuo and H ₂ O (50.0 mL) was added. The reaction mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with EA (4 mL) to give N-(4-fluoro-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (108.9 mg, 38% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.90 (s, 1 H), 9.04 (d, J = 4.8 Hz, 1 H), 8.35 (s, 1 H), 8.28-8.22 (m, 1 H), 8.14-8.09 (m, 2 H), 7.91-7.87 (m, 1 H), 7.48 (s, 1H), 7.32 (s, 1H), 7.26 (t, J = 9.6 Hz, 1H), 4.05–3.90 (m, 4H), 2.85 (s, 3H). LCMS (M+H ⁺ ) m/z: 484.3.

Example 136: N-(4-chloro-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 136) manufacturing

[0839] The preparation of N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide is described in Example 123.

[0840] Step 1: Synthesis of N-(4-chloro-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0841] Pd(dppf)Cl ₂ (87.8 mg, 0.12 mmol)를 디옥산/H ₂ O (5:1) (12 mL) 중 N-(4-클로로-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린아미드 (500 mg, 1.17 mmol), 6-브로모-2-(메틸티오)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘 (348 mg, 1.17 mmol), Cs ₂ CO ₃ (1.14 g, 3.51 mmol)의 혼합물에 N ₂ 하에 첨가하였다. The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was concentrated and purified by silica column chromatography (EA/PE=0% to 80%) to afford N-(4-chloro-3-(2-(methylthio)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d] pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (260 mg, 43% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 517.0.

[0842] Step 2: Synthesis of N-(4-chloro-3-(2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0843] m-CPBA (153 mg, 0.89 mmol) was added in DCM (5 mL) to N-(4-chloro-3-(2-(methylthio)-8,9-dihydroimidazo[1',2 ':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (230 mg, 0.44 mmol) added at 0°C to a mixture of did The reaction mixture was stirred at room temperature for 1 hour, concentrated and N-(4-chloro-3-(2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (244 mg, crude) was obtained as a yield solid, which was obtained without further purification. used in the next step. LCMS (M+H ⁺ ) m/z: 533.1 and 549.1.

[0844] Step 3: Synthesis of N-(4-chloro-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0845] Me-NH ₂ (2 mL) was added to a solution of N-(4-chloro-3-(2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (244 mg, 0.44 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give crude which was purified by preparative-HPLC (0.1% HCOOH) to N-(4-chloro-3-(2-(methylamino)-8,9-dihydroimidazo[1’,2’:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl). ) Picolinamide formate (41 mg, 16.9% yield) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.98 (s, 1H), 9.04 (d, J = 4.8 Hz, 1H), 8.34 (s, 1H), 8.29-8.26 (m, 1H), 8.21 (s, 1H), 8.10 (d, J = 4.8 Hz, 1H) , 8.07 (s, 1H), 7.93 (dd, J = 2.4 Hz, 12.8 Hz, 1H), 7.53–7.51 (m, 2H), 7.28 (s, 1H), 4.10–4.01 (m, 2H), 3.94–3.82 (m, 2H), 2.86 (s, 3H). LCMS (M+H ⁺ ) m/z: 500.3.

Example 137: N-(4-chloro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 137) manufacturing

[0846] The preparation of 6-bromo-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 114.

[0847] Step 1: Synthesis of N-(4-chloro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0848] N-(4- _chloro -3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide (343 mg, 0.80 mmol), Pd(dppf)Cl ₂ (49 mg, 0.067 mmol), Cs ₂ CO ₃ (653 mg, 2.01 mmol) were added. The mixture was stirred under N ₂ at 100° C. for 16 hours. Water (100 mL) was added to the reaction mixture. The mixture was extracted with EA (30 mL x 3). The combined extracts were washed with brine (20 mL x 2), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with MeOH and filtered to give N-(4-chloro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (37.2 mg, 10% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.98 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.34-8.28 (m, 3H), 8.10-8.05 (m, 2H), 7.94-7.91 (m, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.23 (s, 1H), 4.95 (s, 1H), 4.78-4.75 (m, 2H), 4.56-4.53 (m, 2H), 4.04-4.00 (m, 2H), 3.93-3.89 (m, 2H). LCMS (M+H ⁺ ) m/z: 542.4.

Example 138: N-(4-chloro-3-(2-((tetrahydro-2H-pyran-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 138) manufacturing

[0849] The preparation of 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine is described in Example 26.

[0850] Step 1: Synthesis of 6-bromo-N-(tetrahydro-2H-pyran-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-2-amine

[0851] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (200 mg, 0.63 mmol) in THF (15 mL) was added tetrahydro-2H-pyran-4-amine (252 mg, 2.5 mmol). The reaction mixture was stirred at room temperature for 16 hours. H ₂ O (20 mL) was added and the reaction mixture was extracted with EA (20 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give 6-bromo-N-(tetrahydro-2H-pyran-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (237 mg, crude). LCMS (M+H ⁺ ) m/z: 350.0 and 352.0.

[0852] Step 2: Synthesis of N-(4-chloro-3-(2-((tetrahydro-2H-pyran-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0853] To a solution of 6-bromo-N-(tetrahydro-2H-pyran-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (237 mg, 0.67 mmol) in dioxane/H ₂ O (15 mL/5 mL) was added Trimethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinamide (346 mg, 0.81 mmol), Pd(dppf)Cl ₂ (49 mg, 0.067 mmol), Cs ₂ CO ₃ (653 mg, 2.01 mmol) were added. The mixture was stirred under N ₂ at 100° C. for 16 hours. H ₂ O (100 mL) was added and the mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude was triturated with MeOH and filtered to afford N-(4-chloro-3-(2-((tetrahydro-2H-pyran-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (14.7 mg, 4% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 570.4. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.04 (d, J=5.2 Hz, 1 H), 8.38-8.34 (m, 2 H), 8.18 (s, 1 H), 8.09 (d, J=4.4 Hz, 1 H), 8.05-8.04 (m, 1 H), 7.93 (d, J=8.4 Hz, 1 H), 7.55 (d, J=8.4 Hz, 1 H), 7.46-7.36 (m, 1 H), 4.19-4.07 (m, 3 H), 3.96-3.88 (m, 4 H), 3.43-3.33 (m, 2 H), 1.91-1.80 (m, 2 H), 1.57-1.56 (m, 2 H).

Example 139: N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 139) manufacturing

[0854] Step 1: Synthesis of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0855] A mixture of 5-bromo-2-fluoro-4-methylaniline (10 g, 49 mmol), bis(pinacolato)diboron (14.9 g, 58.8 mmol), KOAc (14.4 g, 147 mmol) and Pd(dppf)Cl ₂ (3.59 g, 4.9 mmol) in dioxane (340.0 mL) was degassed with N ₂ After charging 3 times, stirring was performed at 100° C. for 16.0 hours. The reaction mixture was concentrated and purified by column chromatography (PE/EA=4/1) to give 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (12.8 g, crude) as an off-white solid. LCMS (M+H ⁺ ) m/z: 252.2.

[0856] Step 2: Synthesis of 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0857] 디옥산 (70.0 mL) 및 H2O (7.0 mL) 중 2-플루오로-4-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)아닐린 (2.9 g, 11.57 mmol), 6-브로모-N-메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (2.7 g, 9.64 mmol), Cs2CO3 (7.86 g, 24.1 mmol) 및 Pd(dppf)Cl ₂ (706 mg, 0.964 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전한 다음 100℃에서 16.0 시간 교반하였다. The reaction mixture was concentrated and purified by column chromatography (DCM/MeOH=10/1) to give 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (2.01 g, 64.3% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 325.1.

[0858] Step 3: N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0859] A mixture of 4-(trifluoromethyl)picolinic acid (1.01 g, 5.29 mmol) and HATU (2.81 g, 7.4 mmol) in DMF (75.0 mL) was stirred at room temperature for 0.5 h, then 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2, 3-d]pyrimidin-2-amine (1.85 g, 5.716 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was added to water (1.0 L), stirred at room temperature for 0.5 h and then filtered. The collected and filtered cake was purified by column chromatography (DCM/MeOH=15/1, +0.1% NH ₃ -MeOH) to obtain N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (1.709 g, 6 5% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.46 (s, 1 H), 9.05 (d, J=5.2 Hz, 1 H), 8.33 (s, 1 H), 8.24-8.21 (m, 1 H), 8.13-8.12 (m, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.45-7.43 (m, 1H), 7.25 (d, J = 12.0 Hz, 1H), 7.16 (s, 1H), 4.07-3.98 (m, 2H), 3.96-3.88 (m, 2H), 2.84 (d, J = 3.2 Hz, 3H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 498.2.

Example 140: N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 140) manufacturing

[0860] Step 1: Synthesis of 2-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0861] To a solution of 2,2,6,6-tetramethylpiperidine (8.3 g, 59.2 mmol) in dry THF (20 mL) was added n-BuLi (22 mL, 55.5 mmol) at -65 °C under N ₂ . After stirring at -65 °C for 1 hour, 2-fluoro-4-methylbenzonitrile (5.0 g, 37 mmol) in dry THF (10 mL) was added slowly. The mixture was stirred at -65 °C under N ₂ for 1 hour. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.6 g, 51.8 mmol) was added to this mixture. The reaction mixture was stirred at -65 °C for 30 minutes and then warmed to room temperature for 1 hour. Concentration in vacuo and purification on silica gel column chromatography (PE/EA=20:1) gave 2-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (3.84 g, 48.1% yield) as a yellow solid.

[0862] Step 2: Synthesis of 2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzonitrile

[0863] 6-bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3 -d]pyrimidin-2-amine (962 mg, 3.45 mmol), Cs2CO3 (3.7 g, 11.49 mmol), Ruphos (179 mg, 0.383 mmol) and Pd-X-phos G3 (324 mg, 0.383 mmol) were added. The reaction mixture was stirred at 110° C. under N2 for 36 hours. Concentration and purification by silica gel column chromatography (DCM/MeOH=10:1) gave 2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzonitrile (1.0 g, 78.2% yield) as a yellow solid.

[0864] Step 3: Synthesis of methyl 2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzoate

[0865] To a solution of 2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzonitrile (1.0 g, 2.994 mmol) in MeOH (15 mL) was added H2SO4 (3 mL) and the reaction mixture was stirred at 110 °C in a sealed test tube for 3 Stir for 6 hours. Concentration and purification by flash (0.1% NH3H2O) afforded methyl 2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzoate (600 mg, 54.6% yield) as a yellow solid.

[0866] Step 4: Synthesis of 2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzoic acid

[0867] To a solution of methyl 2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzoate (600 mg, 1.635 mmol) in MeOH/HO (5 mL/5 mL) was added LiOH (137 mg, 3.27 mmol). The reaction mixture was stirred at room temperature for 3 hours. Concentration and flash (0.1% NH3H2O) purification afforded 2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzoic acid (350 mg, 60.6%) as a yellow solid.

[0868] Step 5: Synthesis of tert-butyl (2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate

[0869] DPPA (409 mg, 1.49 mmol) and TEA (300 mg, 2.9 8 mmol) was added. The reaction mixture was stirred at 90 °C for 16 hours. Concentration and flash (0.1% NH3H2O) purification afforded tert-butyl (2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (321 mg, 76.4% yield) as a yellow solid.

[0870] Step 6: Synthesis of 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0871] To a solution of tert-butyl (2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (321 mg, 0.757 mmol) in MeOH (2 mL) was added HCl (1 mL). The reaction mixture was stirred at room temperature for 16 hours. Concentration and flash purification (0.1% NH3H2O) afforded 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (150 mg, 46.6% yield) as a yellow solid.

[0872] Step 7: Synthesis of N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0873] 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 0.12 mmol, 1.0 eq) and 4-(trifluoromethyl)picolinic acid (28 mg, 0.30 mmol, 1.2 eq) was added DIEA (0.1 mL) and HATU (70 mg, 0.15 mmol, 1.5 eq). The mixture was stirred overnight at 20 °C. LCMS results confirmed that the reaction performed well. Water was added and the reaction mixture was extracted with EA. The pooled extracts were washed with brine. Concentration and purification by preparative-HPLC (0.1% NH ₄ CO ₃ ) afforded N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (21.0 mg, 35.2%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.04 (d, J = 5.2 Hz, 1H), 8.35 (s, 1H), 8.13-8.12 (m, 2H), 7.93-7.89 (m, 2H), 7.47 (s, 1H), 7.19-7.15 (m, 2H) ), 4.06–3.86 (m, 4H), 3.17 (s, 3H), 2.21 (s, 3H). LCMS (M+H ⁺ ) m/z: 498.1.

Example 141: N-(2- Fluoro -4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)benzamide (compound 141) manufacturing

[0874] Step 1: Synthesis of N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide

[0875] A mixture of benzoic acid (17 mg, 0.139 mmol) and HATU (70 mg, 0.184 mmol) in DMF (3 mL) was stirred at room temperature for 15 minutes, then 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (30 mg, 0.092 mmol) and DIEA (36 mg, 0.276 mmol) were added. The reaction was stirred at room temperature for 16 hours. The resulting mixture was purified by preparative-HPLC (0.1% HCl) to afford N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide (8.8 mg, 22.3% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.17 (s, 1H), 9.96 (s, 1 H), 8.88 (s, 1H), 8.59-8.56 (m, 1H), 8.20 (s, 1H), 7.98-7.96 (m, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.55-7.52 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 4.69-4.64 (m, 2H), 4.04 (t, J = 10.0 Hz, 2H), 2.97 (d, J = 4.8 Hz, 3H), 2.21 (s, 3H). LCMS (M+H ⁺ ) m/z: 429.5.

Example 142 N-(2- Fluoro -4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)picolinamide (compound 142) manufacturing

[0876] Step 1: Synthesis of N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide

[0877] A mixture of picolinic acid (17 mg, 0.139 mmol) and HATU (70 mg, 0.184 mmol) in DMF (3 mL) was stirred at room temperature for 15 minutes, then 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (3 0 mg, 0.092 mmol) and DIEA (36 mg, 0.276 mmol) were added. The reaction was stirred at room temperature for 16 hours. The resulting mixture was purified by preparative-HPLC (0.1% FA) to afford N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide (18.2 mg, 45.8% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.32 (s, 1H), 8.73 (d, J = 4.0 Hz, 1H), 8.25-8.16 (m, 3H), 8.10-8.04 (m, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.49 (br , 1H), 7.23 (s, 1H), 7.15 (d, J = 8.8 Hz, 1H), 4.09–4.00 (m, 2H), 3.92–3.88 (m, 2H), 2.85 (s, 3H), 2.20 (s, 3H). LCMS (M+H ⁺ ) m/z: 430.1.

Example 143 N-(2- Fluoro -4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)but-2-inamide (Compound 143)

[0878] Step 1: Synthesis of N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)but-2-insulfonamide

[0879] To a solution of 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (30 mg 0.092 mmol) in DCM (3 mL) but-2-tinic acid (12 mg, 0.138 mmol), DMAP (22 mg) in DCM (3 mL) , 0.184 mmol) and DCC (28 mg, 0.138 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was purified by preparative-HPLC (0.1% FA) to afford N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)but-2-insulfonamide (13.8 mg, 38.4% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.27 (s, 1H), 8.22-8.19 (m, 2H), 7.49-7.46 (m, 2H), 7.15 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 4.04-3.96 (m, 2 H), 3.89 (d, J = 9.2 Hz, 2H), 2.84 (d, J = 4.0 Hz, 3H), 2.15 (s, 3H), 2.03 (s, 3H). LCMS (M+H ⁺ ) m/z: 391.1.

Example 144: N-(4-chloro-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 144) manufacturing

[0880] Step 1: Synthesis of 5-bromo-4-chloro-2-fluoroaniline

[0881] To a solution of 5-bromo-4-chloro-2-fluorobenzoic acid (1.5 g, 5.9 mmol) and TEA (1.8 g, 17.7 mmol) in DMF (30 mL) was added DPPA (2.44 g, 8.9 mmol) at 0 °C. The solution was stirred at 0° C. under N2 for 3 hours. The solution was then stirred at 80° C. under N2 for 1.5 h. H2O (4.3 g, 236 mmol) was added and the solution was stirred at 100 °C under N2 for 16 h. The reaction solution was diluted with EA (100 mL) and washed with water (30 mL*3). The organic phase was concentrated and purified by silica gel chromatography (PE/EA = 10/1) to give the crude product. The crude was purified again by flash chromatography to give 5-bromo-4-chloro-2-fluoroaniline (140 mg, 10% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 225.9.

[0882] Step 2: Synthesis of 4-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0883] 5-Bromo-4-chloro-2-fluoroaniline (140 mg, 0.623 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (237 mg, 0.935 mmol), KOAc (183 mg, 1.869 mmol) in dioxane (10 mL) ) and Pd(dppf)Cl2 (182 mg, 0.249 mmol) was stirred at 100° C. under N2 for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (PE to PE/EA = 10/1) to give 4-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (169 mg, 100% yield) as a pale green solid. LCMS (M+H+) m/z: 272.1.

[0884] Step 3: Synthesis of 6-(5-amino-2-chloro-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[0885] 4-Chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (140 mg, 0.50 mmol) in dioxane (20 mL) and water (5 mL), 6-bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyridonium A mixture of midin-2-amine (136 mg, 0.50 mmol), Cs2CO3 (488 mg, 1.50 mmol) and Pd(dppf)Cl2 (73 mg, 0.10 mmol) was stirred at 100° C. under N2 for 2 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography to give 6-(5-amino-2-chloro-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (90 mg, 52% yield) as a yellow solid. LCMS (M+H+) m/z: 345.2.

[0886] Step 4: Synthesis of N-(4-chloro-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide hydrochloride

[0887] 6-(5-amino-2-chloro-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 0.116 mmol), 4-(trifluoromethyl)picolinic acid (22 mg, 0.116 mmol) and pyridine (3 drops) in DCM (6 mL) POCl3 (1 volume) was added to the solution. The solution was stirred at room temperature for 15 minutes. The reaction solution was diluted with DCM (30 mL), washed with water (10 mL) and concentrated. The residue was purified by preparative-HPLC (0.1%/HCl/CH3CN/H2O) to afford N-(4-chloro-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide hydrochloride (19.5 mg, 30% yield) as yellow Obtained as a solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.70 (s, 1H), 10.10 (s, 1H), 9.09 (d, J = 5.2 Hz, 1H), 8.91 (s, 1H), 8.63-8.35 (m, 1H), 8.35 (s, 1H), 8.25 ( s, 1H), 8.21–8.17 (m, 2H), 7.90 (d, J = 10.4 Hz, 1H), 4.71–4.61 (m, 2H), 4.10–4.05 (m, 2H), 2.98 (d, J = 4.8 Hz, 3H). LCMS (M+H ⁺ ) m/z: 518.2.

Example 145 N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d] pyrimidin-6-yl)phenyl)-2-( trifluoromethyl ) isonicotinamide (compound 145) manufacturing

[0888] The preparation of 6-bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 133.

[0889] Step 1: Synthesis of 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-2-amine

[0891] 6-Bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (390 mg, 1.39 mmol) in dioxane (20 mL) and water (2 mL), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anyl A mixture of phosphorus (389 mg, 1.67 mmol), Cs ₂ CO ₃ (1.36 g, 4.18 mmol) and Pd(dppf)Cl ₂ (102 mg, 0.14 mmol) was degassed, charged with N ₂ three times and stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by column chromatography (DCM/MeOH=20/1, +0.5% TEA) to give 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (240 mg, 56.3% yield) as a gray solid. LCMS (M+H ⁺ ) m/z: 307.2.

[0891] Step 2: Synthesis of N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)isonicotinamide

[0892] DIEA (50.4 mg, 0.39 mmol) was added to 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 0.13 mmol), 2-(trifluoromethyl)isonicotinic acid (30 mg, 0. 16 mmol) and HATU (74.4 mg, 0.20 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mLx3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product which was purified by preparative-HPLC (0.1% NH _3. H ₂ O) to give N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1’,2’:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)- Obtained 2-(trifluoromethyl)isonicotinamide (4.7 mg, 6.0 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.64 (s, 1H), 8.98 (d, J = 5.2 Hz, 1H), 8.37 (s, 1H), 8.26-8.18 (m, 2H), 7.67 (dd, J = 8.4, 2.0 Hz, 1H), 7.63-7.62 (m, 1H), 7.41-7.39 (m, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 4.01-4.00 (m, 2H), 3.93-3.91 (m, 2H), 2.84 (d, J = 4.0 Hz, 3H) 2.21 (s, 3H). LCMS (M+H ⁺ ) m/z: 480.2.

Example 146 N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d] pyrimidin-6-yl)phenyl)-6-( trifluoromethyl ) pyrazine -2- carboxamide (compound 146) manufacturing

[0893] Step 1: Synthesis of ethyl 6-(trifluoromethyl)pyrazine-2-carboxylate

[0894] A mixture of 2-chloro-6-(trifluoromethyl)pyrazine (400 mg, 2.2 mmol), AcOK (647 mg, 6.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (161 mg, 0.22 mmol) in EtOH (15.0 mL). The obtained mixture was degassed, charged with N ₂ three times, and then stirred at 80° C. for 4 hours. The reaction mixture was concentrated and purified by silica column (PE:EA=5:1) to give ethyl 6-(trifluoromethyl)pyrazine-2-carboxylate (560 mg, 93% yield) as a yellow oil. LCMS (M+H ⁺ ) m/z: 221.0.

[0895] Step 2: Synthesis of 6-(trifluoromethyl)pyrazine-2-carboxylic acid

[0896] A mixture of ethyl 6-(trifluoromethyl)pyrazine-2-carboxylate (510 mg, 2.32 mmol) and LiOH-H ₂ O (584 mg, 13.9 mmol) in THF (10.0 mL) and H ₂ O (10.0 mL) was stirred at 25 °C for 2.5 h. 2 N HCl was then added to the reaction mixture to make pH=5-6 and the reaction mixture was extracted with EA (50 mL x2). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 6-(trifluoromethyl)pyrazine-2-carboxylic acid (410 mg, 93% yield) as an off-white solid. LCMS (MH)-m/z: 191.1.

[0897] Step 3: Synthesis of N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-6-(trifluoromethyl)pyrazine-2-carboxamide

[0898] 6-(trifluoromethyl)pyrazine-2-carboxylic acid (36 mg, 0.187 mmol), 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.196 mmol) and HATU (1 42 mg, 0.374 mmol) was added DIEA (48 mg, 0.374 mmol). The resulting mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was added slowly to water (40.0 mL), stirred at room temperature for 30 minutes, then filtered. The collected cake was purified by silica column chromatography (DCM:MeOH=15:1, +0.1% NH ₃ -MeOH) to obtain N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-6-(trifluoromethyl)pyrazine-2-carboxamide (45.9 mg, 51% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (s, 1 H), 9.54 (s, 1 H), 9.44 (s, 1 H), 8.25-8.22 (m, 1 H), 7.77 (d, J=7.6 Hz, 1 H), 7.72 (s, 1 H), 7.43-7.41 (m, 1 H), 7.25 (d, J=8.0 Hz, 1 H), 7.15 (s, 1 H), 4.07-4.01 (m, 2 H), 3.93-3.89 (m, 2 H), 2.85 (s, 3 H), 2.21 (s, 3 H). LCMS (M+H ⁺ ) m/z: 481.4.

Example 147 N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d] pyrimidin-6-yl)phenyl)-2-( trifluoromethyl )pyrimidine-4- carboxamide (compound 147) manufacturing

[0899] Step 1: Synthesis of ethyl 2-(trifluoromethyl)pyrimidine-4-carboxylate

[0900] A mixture of 4-chloro-2-(trifluoromethyl)pyrimidine (150 mg, 0.55 mmol), AcOK (162 mg, 1.65 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (45 mg, 0.055 mmol) in EtOH (15.0 mL) was degassed and charged three times with N ₂ and then charged with 8 It was stirred for 4 hours at 0°C. The reaction mixture was concentrated and purified by silica column chromatography (PE:EA=5:1) to give ethyl 2-(trifluoromethyl)pyrimidine-4-carboxylate (144 mg, 80% yield) as a yellow oil. LCMS (M+H ⁺ ) m/z: 221.0.

[0901] Step 2: Synthesis of 2-(trifluoromethyl)pyrimidine-4-carboxylic acid

[0902] To a solution of ethyl 2-(trifluoromethyl)pyrimidine-4-carboxylate (144 mg, 0.65 mmol) in THF (3.0 mL) and H ₂ O (3.0 mL) was added LiOH-H ₂ O (165 mg, 3.93 mmol). The resulting mixture was stirred at 25°C for 2.5 hours. 2 N HCl was then added to the reaction mixture to make pH=5-6 and the reaction mixture was extracted with EA (50 mL x2). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 2-(trifluoromethyl)pyrimidine-4-carboxylic acid (98 mg, 78% yield) as an off-white solid. LCMS (MH ^- ) m/z: 191.1.

[0903] Step 3: Synthesis of N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)pyrimidine-4-carboxamide

[0904] 2-(trifluoromethyl)pyrimidine-4-carboxylic acid (36 mg, 0.187 mmol), 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.196 mmol) and HATU (1 in DMF (3.0 mL)) 42 mg, 0.374 mmol) was added DIEA (48 mg, 0.374 mmol). The resulting mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was added slowly to water (40 mL), stirred at room temperature for 30 minutes and filtered. The collected cake was purified by silica column chromatography (DCM:MeOH=15:1, +0.1% NH ₃ -MeOH) to obtain N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)pyrimidine-4-carboxamide (29.6 mg, 33% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ10.64 (s, 1 H), 9.34 (d, J=4.8 Hz, 1 H), 8.34 (d, J=4.8 Hz, 1 H), 8.22-8.21 (m, 1 H), 7.78-7.75 (m, 1 H), 7.73 (s, 1 H), 7.45-7.42 (m, 1 H), 7.26 (d, J=8.0 Hz, 1 H), 7.16 (s, 1 H), 4.12-3.99 (m, 2 H), 3.93-3.89 (m, 2 H), 2.84 (s, 3 H), 2.21 (s, 3 H). LCMS (M+H ⁺ ) m/z: 481.2.

Example 148: N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)pyrimidine-2-carboxamide (compound 148) manufacturing

[0905] Step 1: Synthesis of N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)pyrimidine-2-carboxamide

[0906] A mixture of 4-(trifluoromethyl)pyrimidine-2-carboxylic acid (35 mg, 0.18 mmol) in SOCl2 (1.0 mL) was stirred at 80 °C for 2 h. The reaction mixture was concentrated and diluted with DCM (2.0 mL) then a solution of DIPEA (58 mg, 0.45 mmol) and 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (45 mg, 0.15 mmol) in DCM (4.0 mL) was added. The reaction mixture was stirred at 10 °C for 2 hours. The reaction mixture was concentrated and purified by column chromatography (DCM: MeOH=10:1) and preparative-HPLC (NH4HCO3) to N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)pyrimidine-2-carboxamide (11.4 mg, 16% yield) was obtained. ¹ HNMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H), 9.39 (d, J = 5.2 Hz, 1H), 8.35 (s, 1H), 8.27 (d, J = 5.2 Hz, 1H), 7.77-7.75 (m, 2H), 7.37-7.27 (m, 3H), 4.20–4.05 (m, 2H), 3.96–3.91 (m, 2H), 2.87 (s, 3H), 2.21 (s, 3H). LCMS (M+H ⁺ ) m/z: 481.0.

Example 149: N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (compound 149) manufacturing

[0907] Step 1: Synthesis of 3-chloro-5- (trifluoromethyl) pyridazine

[0908] A mixture of 5-(trifluoromethyl)pyridazin-3-ol (200 mg, 1.2 mmol) in POCl ₃ (1.0 mL) was stirred at 110 °C for 2 h. The reaction mixture was poured into cold water and the pH was adjusted to 7 with 2N NaOH (aq). The reaction mixture was extracted with DCM (100 mL x 5) and the combined organic phases were purified by column chromatography (PE: EA=2:1) to give 3-chloro-5-(trifluoromethyl)pyridazine (100 mg, 48% yield) as a solid. LCMS (M+H ⁺ ) m/z: 184.0.

[0909] Step 2: Synthesis of methyl 5-(trifluoromethyl)pyridazine-3-carboxylate

[0910] A mixture of 3-chloro-5-(trifluoromethyl)pyridazine (182 mg, 1.0 mmol), DIPEA (400 mg, 3.0 mmol), Pd(dppf)Cl ₂ (73 mg, 0.1 mmol) in MeOH (15 mL) was stirred under a CO balloon at 80 °C for 24 h. The mixture was purified by column chromatography (PE: EA=10:1) to give methyl 5-(trifluoromethyl)pyridazine-3-carboxylate (35 mg) as a white solid. LCMS (M+H ⁺ ) m/z: 207.1.

[0911] Step 3: Synthesis of 5-(trifluoromethyl)pyridazine-3-carboxylic acid

[0912] A mixture of methyl 5-(trifluoromethyl)pyridazine-3-carboxylate (35 mg, 0.15 mmol) and LiOH.H ₂ O (18 mg, 0.45 mmol) in THF (2.5 mL) and water (2.5 mL) was stirred at 20 °C for 2 h. The pH was adjusted to 5 with 3 M HCl and the reaction mixture was extracted with EA (20 mLx2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the product 5-(trifluoromethyl)pyridazine-3-carboxylic acid (30 mg, 100% yield). LCMS (M+H ⁺ ) m/z: 193.0.

[0913] Step 4: Synthesis of N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide

[0914] A mixture of 5-(trifluoromethyl)pyridazine-3-carboxylic acid (30 mg, 0.15 mmol) in SOCl ₂ (1.0 mL) was stirred at 80 °C for 2 h. The reaction mixture was concentrated and diluted with DCM (2.0 mL), then a solution of DIPEA (47 mg, 0.36 mmol), 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (38 mg, 0.12 mmol) in DCM (4.0 mL) was added. The reaction mixture was stirred at 10 °C for 2 hours. The reaction mixture was concentrated and purified by preparative-HPLC (NH4HCO3) to afford N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (23 mg, 40% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6): 11.24 (s, 1H), 9.96 (d, J = 1.6 Hz, 1H), 8.56 (d, J = 1.2 Hz, 1H), 8.29 (s, 1H), 7.86 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.49 (br, 1H), 7.28-7.25 (m, 2H), 4.14-4.01 (m, 2H), 3.96-3.90 (m, 2H), 2.86 (s, 3H), 2.19 (s, 3H). LCMS (M+H ⁺ ) m/z: 481.0.

Example 150: N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (compound 150) manufacturing

[0915] Step 1: Synthesis of methyl 6-iodopyridazine-4-carboxylate

[0916] A solution of methyl 6-chloropyridazine-4-carboxylate (250 mg, 1.44 mmol) and NaI (314 mg, 2.10 mmol) in HI (2.0 mL) was stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with water (15 mL). The mixture was made basic to pH=7 with saturated aqueous sodium bicarbonate solution and extracted with DCM (20 mLx2). The combined organic layers were washed with brine (20 mL), Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash (PE: EA=5:1) to give methyl 6-iodopyridazine-4-carboxylate (188 mg, purity: 52%) as a white solid. LCMS (M+H ⁺ ) m/z: 265.0.

[0917] Step 2: Synthesis of 6-(trifluoromethyl)pyridazine-4-carboxylate

[0918] A mixture of methyl 6-iodopyridazine-4-carboxylate (188 mg, 0.70 mmol) and (1,10-phenanthroline)(trifluoromethyl)copper (I) (218 mg, 0.70 mmol) in DMF (5 mL) was stirred at 20 °C for 1 h in the dark. The reaction mixture was quenched with water (20 mL) and extracted with EA (10 mLx2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash (PE: EA=5:1) to give 6-(trifluoromethyl)pyridazine-4-carboxylate (50 mg purity: 35%) as an off-white solid. LCMS (M+H+) m/z: 207.1.

[0919] Step 3: Synthesis of 6-(trifluoromethyl)pyridazine-4-carboxylic acid

[0920] A mixture of methyl 6-(trifluoromethyl)pyridazine-4-carboxylate (100 mg, 0.5 mmol) and LiOH.H ₂ O (60 mg, 1.5 mmol) in THF (2.5 mL) and water (2.5 mL) was stirred at 20 °C for 2 h. The mixture was acidified to pH=5 with 3 M HCl and extracted with EA (20 mLx2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give 6-(trifluoromethyl)pyridazine-4-carboxylic acid (92 mg, 100% yield). LCMS (M+H ⁺ ) m/z: 193.0.

[0921] Step 4: Synthesis of N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0922] A mixture of 6-(trifluoromethyl)pyridazine-4-carboxylic acid (46 mg, 0.24 mmol) in SOCl ₂ (1.0 mL) was stirred at 80 °C for 2 h. The reaction mixture was concentrated and diluted with DCM (2.0 mL) then a solution of DIPEA (78 mg, 0.60 mmol), 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.20 mmol) in DCM (4.0 mL) was added. The reaction mixture was stirred at 10 °C for 2 hours. The reaction was concentrated and purified by flash (DCM: MeOH=10:1) and preparative-HPLC (NH ₄ HCO ₃ ) to N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (23.2 mg , 24% yield) was obtained. ^1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 9.92 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.26 (br, 1H), 7.69-7.64 (m, 3H), 7.29-7.27 (m, 2H), 4.10–4.00 (m, 2H), 3.96–3.89 (m, 2H), 2.85 (s, 3H), 2.19 (s, 3H). LCMS (M+H ⁺ ) m/z: 481.0.

Example 151: N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (compound 151) manufacturing

[0923] Step 1: Synthesis of ethyl 6-(trifluoromethyl)pyrimidine-4-carboxylate

[0924] A mixture of 4-chloro-6-(trifluoromethyl)pyrimidine (1 g, 5.5 mmol), AcOK (2.156 g, 22 mmol), and Pd(dppf)Cl ₂ (200 mg, 0.27 mmol) in EtOH (30 mL) was degassed, charged with CO three times and stirred at 80 °C for 16 h under CO. The reaction mixture was concentrated and purified by silica column chromatography (PE:EA=4:1) to give ethyl 6-(trifluoromethyl)pyrimidine-4-carboxylate (230 mg, 19% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 221.2.

[0925] Step 2: Synthesis of 6-(trifluoromethyl)pyrimidine-4-carboxylic acid

[0926] A mixture of ethyl 6-(trifluoromethyl)pyrimidine-4-carboxylate (100 mg, 0.45 mmol), LiOH (76 mg, 2.72 mmol) in THF (5 mL) and H ₂ O (0.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with H ₂ O (20 mL) and the pH was adjusted to 4-5 with HCl (2M). The reaction mixture was extracted with EA (20 mLx2). The organic layer was dried over NaSO ₄ , filtered and concentrated to give 6-(trifluoromethyl)pyrimidine-4-carboxylic acid (70 mg, crude) as a brown solid. LCMS (M+H ⁺ ) m/z: 193.0.

[0927] Step 3: Synthesis of N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide

[0928] 6-(trifluoromethyl)pyrimidine-4-carboxylic acid (60 mg, crude), 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (100 mg, 0.33 mmol), and HATU (248 mg) in DMF (3.0 mL) , 0.65 mmol) was added DIEA (84 mg, 0.65 mmol). The resulting mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was slowly added to water (40 mL), stirred at room temperature for 30 minutes, and filtered. The collected cake was purified by silica column chromatography (DCM:MeOH=15:1, +0.1% NH ₃ -MeOH) to obtain N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide (32.8 mg, 1 0.5 % yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.97 (s, 1 H), 9.68 (s, 1 H), 8.45 (s, 1 H), 8.26-8.24 (m, 1 H), 7.82 (s, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.57-7.45 (m, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 7.17-7.16 (m, 1H), 4.11-4.02 (m, 2 H), 3.98 (t, J = 8.8 Hz, 2 H), 2.86 (s, 3 H), 2.22 (s, 3 H). LCMS (M+H ⁺ ) m/z: 481.7.

Example 152: 3-chloro-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 152) manufacturing

[0929] Step 1: Synthesis of 3-chloro-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0930] 3-chloro-4-(trifluoromethyl)picolinic acid (40 mg, 0.18 mmol), HATU (68 mg, 0.18 mmol), DIPEA (58 mg, 0.45 mmol) and 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2, A mixture of 3-d]pyrimidin-2-amine (46 mg, 0.15 mmol). When the reaction mixture was stirred at 10 °C for 2 hours, the reaction was confirmed by LCMS to be complete. The reaction was purified by flash (DCM: MeOH=10:1) followed by prep-HPLC (0.5%FA) to give 3-chloro-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (5.3 mg) as a yellow solid. . ^1H NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H), 8.88 (d, J = 4.8 Hz, 1H), 8.29-8.28 (m, 1H), 8.06 (d, J = 4.8 Hz, 1H), 7.64-7.53 (m, 3H), 7.26-7.2 4 (m, 2H), 4.02–3.94 (m, 2H), 3.91–3.89 (m, 2H), 2.85 (s, 3H), 2.19 (s, 3H). LCMS (M+H ⁺ ) m/z: 513.9

Example 153: N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (compound 153) manufacturing

[0931] Step 1: Synthesis of 2-oxo-5-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid

[0932] 3-Bromo-5-(trifluoromethyl)pyridin-2-ol (960 mg, 4.0 mmol) was added portionwise to a suspension of NaH (180 mg, 4.4 mmol) in anhydrous THF (20 mL). After completion of the addition of the intermediate, the reaction mixture was cooled to -78 °C and treated with tert-butyllithium (3.2 mL, 8.0 mmol) dropwise via syringe. After stirring for 5 minutes, DMF (1.0 mL, 12.0 mmol) was slowly added to keep the temperature below -50 °C. Then, the resulting mixture was stirred for 10 hours and heated to room temperature. The mixture was quenched with 2N HCl then diluted with ethyl acetate (30 mL). The organic layer was separated, washed with brine, dried over MgSO ₄ and evaporated in vacuo. The desired product was precipitated from ethyl acetate and hexanes and filtered to give a light brown solid 2-oxo-5-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid (260 mg, 23.8% yield). 1H NMR (400 MHz, CD ₃ OD): 10.13 (s, 1H), 8.21 (s, 2H). LCMS (M+H ⁺ ) m/z: 208.0.

[0933] Step 2: Synthesis of N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide

[0934] A mixture of 2-oxo-5-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid (37 mg, 0.18 mmol) in SOCl2 (1.0 mL) was stirred at 80 °C for 2 h. The reaction mixture was concentrated and diluted with DCM (2.0 mL) then a solution of DIPEA (58 mg, 0.45 mmol), 6-(5-amino-2-methylphenyl) -N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (45 mg, 0.15 mmol) in DCM (4.0 mL) was added. The reaction mixture was stirred at 10 °C for 2 hours, concentrated, purified by flash (DCM: MeOH=10:1) and preparative-HPLC to N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridine. -3-carboxamide (11.8 mg, 16% yield) was obtained. 1H NMR (400 MHz, DMSO-d6): 12.12 (s, 1H), 8.53-8.34 (m, 3H), 8.05-8.02 (m, 1H), 7.67-7.58 (m, 3H), 7.31-7.28 (m, 1H), 4.34-4.32 (m, 2H) , 3.96–3.92 (m, 2H), 2.90 (s, 3H), 2.19 (s, 3H). LCMS (M+H+) m/z: 496.0.

Example 154 N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)piperidine-2-carboxamide (compound 154) manufacturing

[0935] Step 1: Synthesis of 4-(trifluoromethyl)piperidine-2-carboxylic acid

[0936] A mixture of 4-(trifluoromethyl)picolinic acid (191 mg, 1.0 mmol), PtO ₂ (45 mg, 0.2 mmol) in MeOH (6.0 mL) and aq HCl (1 drop) was stirred at 70 °C under H2 for 16 h. The reaction mixture was filtered and the filtrate was concentrated to give crude 4-(trifluoromethyl)piperidine-2-carboxylic acid which was used directly in the next step. LCMS (M+H ⁺ ) m/z: 198.1.

[0937] Step 2: Synthesis of 1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidine-2-carboxylic acid

[0938] A mixture of 4-(trifluoromethyl)piperidine-2-carboxylic acid (200 mg, 1.0 mmol), Boc ₂ O (260 mg, 1.2 mmol) in MeOH (6.0 mL) and aq Na ₂ CO ₃ (2.0 mL) was stirred at 80 °C for 2 h. The pH was adjusted to 6.0 with citric acid aq (4.0 mL). The reaction mixture was extracted with EA (30 mL x 2). The combined organic phases were dried over Na ₂ SO ₄ and concentrated to give 1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidine-2-carboxylic acid (188 mg, 60% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 198.1.

[0939] Step 3: Synthesis of tert-butyl 2-((4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-4-(trifluoromethyl)piperidine-1-carboxylate

[0940] 1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidine-2-carboxylic acid (90 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol), DIPEA (97 mg, 0.75 mmol), 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimida in DCM (6.0 mL) A mixture of crude[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (77 mg, 0.25 mmol) was stirred at 10° C. for 2 h. Water was added and the reaction mixture was extracted with EA. The pooled extracts were washed with brine. Concentrated and purified by flash (DCM: MeOH=20:1) to obtain tert-butyl 2-((4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-4-(trifluoromethyl)piperidine-1-carboxylate (85 mg, 50% yield) Obtained as a rule solid. LCMS (M+H ⁺ ) m/z: 586.3.

[0941] Step 4: Synthesis of N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)piperidine-2-carboxamide

[0942] To a mixture of tert-butyl 2-((4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamoyl)-4-(trifluoromethyl)piperidine-1-carboxylate (85 mg, 0.15 mmol) in DCM (3.0 mL), FA (1.0 mL) was added. The mixture was stirred at 10 °C for 1 hour. The reaction was concentrated and diluted with DCM and water. The pH was adjusted to 8.0 with Na ₂ CO ₃ aq (0.5 mL), the organic phase was concentrated and purified by preparative-HPLC (NH ₄ HCO ₃ ), N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1’,2’:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)piperidine Obtained -2-carboxamide (12.0 mg, 18% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): 9.75 (s, 1H), 8.26 (s,1H), 7.52-7.49 (m, 3H), 7.17-7.15 (m, 2H), 4.11-4.02 (m, 2H), 4.00-3.88 (m, 2H), 3.14-3.11 (m, 1H), 2.83 (d, J= 11.2 Hz, 3H), 2.67-2.62 (m, 3H), 2.43 (s, 3H), 2.02-2.01 (m, 1H), 1.75-1.74 (m, 1H), 1.35-1.30 (m, 2H). LCMS (M+H ⁺ ) m/z: 486.1.

Example 155 N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)piperidine-4-carboxamide (compound 155) manufacturing

[0943] Step 1: Synthesis of 2-(trifluoromethyl)piperidine-4-carboxylic acid

[0944] To a solution of 2-(trifluoromethyl)isonicotinic acid (382 mg, 2 mmol) in EtOH (10 mL) was added PtO2 (40 mg, 10% w/w %) and the reaction mixture was stirred at 80° C. for 4 h under a hydrogen atmosphere. LCMC results indicated that the reaction was complete. The reaction mixture was filtered through celite and the filtrate was concentrated to give 2-(trifluoromethyl)piperidine-4-carboxylic acid as a white solid (250 mg, crude) which was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 198.0.

[0945] Step 2: Synthesis of N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)piperidine-4-carboxamide

[0946] 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (110 mg, 0.27 mmol), DIEA (70 mg, 0.54 mmol) and HATU (154 mg. 0.41 mmol) were added. The mixture was stirred at 25 °C for 1 hour. LCMC results indicated that the reaction was complete. The mixture was diluted with water (10 mL) and extracted with DCM (10 mLx 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by preparative-HPLC to obtain N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)piperidine-4- Carboxamide (19.3 mg) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 8.25 (s, 1H), 7.57 -7.37 (m, 3H), 7.14 (d, J = 8.1 Hz, 2H), 4.04 (d, J = 34.6 Hz, 2H), 3.90 (t, J = 9.4 Hz, 2 H), 3.32 (s, 1H), 3.26 (s, 1H), 3.05 (d, J = 11.6 Hz, 1H), 2.84 (s, 3H), 2.58 (d, J = 12.5 Hz, 1H), 2.15 (s, 3H), 1.86 (d, J = 12.1 Hz, 1H), 1 .73 (d, J = 11.3 Hz, 1H), 1.45 (dt, J = 12.2, 8.4 Hz, 2H). LCMS (M+H ⁺ ) m/z: 486.1.

Example 156: 1-methyl-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)piperidine-4-carboxamide (compound 156) manufacturing

[0947] Step 1: Synthesis of 2-(trifluoromethyl)piperidine-4-carboxylic acid

[0948] To a solution of 2-(trifluoromethyl)isonicotinic acid (382 mg, 2 mmol) in EtOH (10 mL) was added PtO2 (40 mg, 10% w/w %) and the reaction mixture was stirred at 80° C. for 4 h under a hydrogen atmosphere. LCMC results indicated that the reaction was complete. The reaction mixture was filtered through celite and the filtrate was concentrated to give 2-(trifluoromethyl)piperidine-4-carboxylic acid as a white solid (250 mg, crude) which was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 198.0.

[0949] Step 2: Synthesis of 1-methyl-2-(trifluoromethyl)piperidine-4-carboxylic acid

[0950] To a solution of 2-(trifluoromethyl)piperidine-4-carboxylic acid (80 mg, 0.4 mmol) in MeOH (2 mL) was added HCHO (30% in water) (100 mg, 1 mmol) and NaCNBH3 (126 mg, 2 mmol) and the reaction mixture was stirred at 25 °C for 3 h. LCMC results indicated that the reaction was complete. The reaction mixture was filtered through celite, the filtrate was concentrated and the residue was diluted with water (10 mL), extracted with EA (10 mL*3), dried over anhydrous Na2SO4, filtered and concentrated to give 1-methyl-2-(trifluoromethyl)piperidine-4-carboxylic acid (60 mg, crude) which was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 212.1.

[0951] Step 3: Synthesis of 1-methyl-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)piperidine-4-carboxamide

[0952] To a solution of 1-methyl-2-(trifluoromethyl)piperidine-4-carboxylic acid (40 mg, crude) in DCM (2 mL) was added oxalyl chloride (127 mg, 1 mmol) and the reaction mixture was stirred at 25 °C for 1 hour. LCMC results indicated that the reaction was complete. The reaction mixture was concentrated to give crude 1-methyl-2-(trifluoromethyl)piperidine-4-carbonyl chloride. A mixture of 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (61 mg, 0.2 mmol) and DIEA (52 mg, 0.4 mmol) in DCM (1 mL) was mixed with crude 1-methyl-2-(trifluoromethyl)piperidine-4-carb in DCM (1 mL). It was added to a solution of bornyl chloride. The mixture was stirred at 25 °C for 1 hour. LCMC results indicated that the reaction was complete. The mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid which was purified by preparative-HPLC to obtain 1-methyl-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)piperi Obtained din-4-carboxamide (12.4 mg, 12% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.50 (br, 2H), 7.44 (dd, J = 8.4, 2.4 Hz, 1H), 7.20 (br, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.11-4.01 (m, 2H), 3.90 (t, J = 9.2 Hz, 2H), 2.92 (d, J = 11.6 Hz, 1H), 2.85-2.80 (m, 4H), 2.43 (d, J = 12.0 Hz, 1H), 2.30-2.28 (m, 4H), 2.15 (s, 3H), 1.93 (d, J = 12.4 Hz, 1H), 1.77 (d, J = 12.4 Hz, 1H), 1.60-1.55 (m, 2H). LCMS (M+H ⁺ ) m/z: 500.2.

Example 157: 6-(4-methyl-1H-imidazol-1-yl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 157) manufacturing

[0953] Step 1: Synthesis of ethyl 4-(trifluoromethyl)picolinate

[0954] A mixture of 4-chloro-6-(trifluoromethyl)pyrimidine (2 g, 8.85 mmol), AcOK (3.47 g, 35.4 mmol), and Pd(dppf)Cl ₂ (300 mg, 0.5 mmol) in EtOH (30 mL) was degassed, charged with CO three times and then stirred at 80 °C for 16 h under CO. The reaction mixture was concentrated and purified by silica column (PE:EA=3:1) to give ethyl 4-(trifluoromethyl)picolinate (1.72 g, 88 % yield) as a brown oil. LCMS (M+H ⁺ ) m/z: 220.0.

[0955] Step 2: Synthesis of 2-(ethoxycarbonyl)-4-(trifluoromethyl)pyridine 1-oxide

[0956] To a mixture of ethyl 4-(trifluoromethyl)picolinate (1.72 g, 7.8 mmol) and urea hydrogen peroxide (1.48 g, 15.7 mmol) in DCM was added TFAA (3.3 g, 15.7 mmol). The mixture was stirred at room temperature for 16 hours, concentrated and then purified by silica column chromatography (PE:EA=3:1) to give 2-(ethoxycarbonyl)-4-(trifluoromethyl)pyridine 1-oxide (1.8 g, 98 % yield) as a brown oil. LCMS (M+H ⁺ ) m/z: 236.1.

[0957] Step 3: Synthesis of ethyl 6-chloro-4- (trifluoromethyl) picolinate

[0958] A mixture of 2-(ethoxycarbonyl)-4-(trifluoromethyl)pyridine 1-oxide (1.8 g, 7.76 mmol) in POCl ₃ (30 mL) was stirred at 100 °C for 5 h. The reaction mixture was concentrated and NaHCO ₃ aq. (10 mL) and extracted with EA (20 mL x 2). The organic layer was dried over NaSO ₄ , filtered and concentrated. The residue was purified by silica column chromatography (PE:EA=3:1) to give ethyl 6-chloro-4-(trifluoromethyl)picolinate (1.8 g, 92% yield) as a brown oil. LCMS (M+H ⁺ ) m/z: 254.2.

[0959] Step 4: Synthesis of 6-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)picolinic acid

[0960] A mixture of ethyl 6-chloro-4-(trifluoromethyl)picolinate (100 mg, 0.40 mmol), 4-methyl-1H-imidazole (66 mg, 0.80 mmol) and K ₂ CO ₃ (109 mg, 0.80 mmol) in DME (5 mL) was stirred at 140 °C for 4 h under N ₂ . The reaction mixture was concentrated and dissolved in MeOH (5 mL), NaOH (16 mg, 0.40 mmol) was added and the mixture was stirred at room temperature for 0.5 h. The mixture was diluted with H ₂ O (20 mL) and the pH was adjusted to 4-5 with HCl (2 M), then extracted with EA (30 mL x 2). The organic layer was dried over NaSO ₄ , filtered and concentrated in vacuo to give 6-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)picolinic acid (80 mg, crude) as a brown oil. LCMS (MH ⁺ ) m/z: 270.1.

[0961] Step 5: Synthesis of 6-(4-methyl-1H-imidazol-1-yl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0962] 6-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)picolinic acid (80 mg, crude), 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (90 mg, 0.3 0 mmol), and HATU (224 mg, 0.59 mmol) was added DIEA (76 mg, 0.59 mmol). The resulting mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was slowly added to water (40.0 mL), stirred at room temperature for 30 minutes, and filtered. The collected cake was purified by silica column chromatography (DCM:MeOH=15:1, +0.1% NH ₃ -MeOH) to obtain 6-(4-methyl-1H-imidazol-1-yl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoro Methyl)picolinamide (10.2 mg, 6.2 % yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.55 (s, 1H), 9.03 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 8.19 (s, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.68-7.48 (m, 1H), 7.32-7.27 (m, 2H), 4.21-4.05 (m, 2H), 3.96-3.94 (t, J = 8.8 Hz, 2H), 2.87 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H). LCMS (M+H ⁺ ) m/z: 560.4.

Example 158: 5-((4-ethylpiperazin-1-yl)methyl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 158) manufacturing

[0963] Step 1: Synthesis of (6-chloro-4-(trifluoromethyl)pyridin-3-yl)methanol

[0964] BH ₃ to a mixture of 6-chloro-4-(trifluoromethyl)nicotinic acid (400 mg, 1.78 mmol) in THF (10 mL) ^. THF (2M, 1.78 mL) was added dropwise at room temperature. The mixture was stirred at 80 °C for 4 hours. The reaction mixture was quenched with water (20 mL) and extracted with DCM (20 mL). The organic phase was concentrated in vacuo and the residue was purified by column chromatography on silica column chromatography (PE:EA=4:1) to give (6-chloro-4-(trifluoromethyl)pyridin-3-yl)methanol (360 mg, 96 % yield) as a yellow oil. LCMS (M+H ⁺ ) m/z: 212.0.

[0965] Step 2: Synthesis of (6-chloro-4-(trifluoromethyl)pyridin-3-yl)methyl methanesulfonate

[0966] To a mixture of (6-chloro-4-(trifluoromethyl)pyridin-3-yl)methanol (200 mg, 0.95 mmol) in THF (10 mL) was added MsCl (218 mg, 1.895 mmol) dropwise at 0 °C. The mixture was stirred at 30 °C for 4 hours. The reaction mixture was diluted with DCM (20 mL) and washed with brine (10 mL x 2). The organic phase was dried over NaSO ₄ , filtered, and concentrated in vacuo to give (6-chloro-4-(trifluoromethyl)pyridin-3-yl)methyl methanesulfonate (240 mg, crude) as a yellow solid. LCMS (M+H ⁺ ) m/z: 289.8.

[0967] Step 3: Synthesis of 1-((6-chloro-4-(trifluoromethyl)pyridin-3-yl)methyl)-4-ethylpiperazine

[0968] (6-chloro-4-(trifluoromethyl)pyridin-3-yl)methyl methanesulfonate (240 mg, crude) and K ₂ CO ₃ in CH3CN (10 mL) (433 mg, 3.80 mmol) was added 1-ethylpiperazine (197 mg, 1.425 mmol). The mixture was stirred at 80 °C for 4 hours and concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH=10:1) to give 1-((6-chloro-4-(trifluoromethyl)pyridin-3-yl)methyl)-4-ethylpiperazine (180 mg, 51% yield) as a brown oil. LCMS (M+H ⁺ ) m/z: 308.1.

[0969] Step 4: Synthesis of ethyl 5-((4-ethylpiperazin-1-yl)methyl)-4-(trifluoromethyl)picolinate

[0970] 1-((6-chloro-4-(trifluoromethyl)pyridin-3-yl)methyl)-4-ethylpiperazine (180 mg, 0.59 mmol) in EtOH (20 mL), AcOK (230 mg, 2.35 mmol) and Pd(dppf)Cl ₂ (21 mg, 0.03 mmol) was degassed, charged with CO three times and stirred under CO at 80° C. for 16 h. The reaction mixture was concentrated and purified by column chromatography on silica gel (DCM:MeOH=15:1) to give ethyl 5-((4-ethylpiperazin-1-yl)methyl)-4-(trifluoromethyl)picoli Nate (180 mg, 88 % yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 346.2.

[0971] Step 5: Synthesis of 5-((4-ethylpiperazin-1-yl)methyl)-4-(trifluoromethyl)picolinic acid

[0972] LiOH (6.9 mg, 1.45 mmol) was added to a mixture of ethyl 5-((4-ethylpiperazin-1-yl)methyl)-4-(trifluoromethyl)picolinate (100 mg, 0.29 mmol) in THF:H ₂ O (5:1) (5 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with DCM (20 mL). The pH of the aqueous phase was adjusted to 3 with 2N HCl and then concentrated to give concentrated and 5-((4-ethylpiperazin-1-yl)methyl)-4-(trifluoromethyl)picolinic acid (150 mg, crude) as a white solid. LCMS (M+H ⁺ ) m/z: 318.2.

[0973] Step 6: Synthesis of 5-((4-ethylpiperazin-1-yl)methyl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[0975] 5-((4-ethylpiperazin-1-yl)methyl)-4-(trifluoromethyl)picolinic acid (25 mg, 0.078 mmol), 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (20 mg, 0.078 mmol) in DMF (1 mL) 065 mmol) and DIEA (25 mg, 0.20 mmol) was added HATU (37 mg, 0.098 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mLx3). The combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give crude which was purified by preparative-HPLC (0.1% NH ₃ .H ₂ O) to obtain 5-((4-ethylpiperazin-1-yl)methyl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6] Obtained pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (12.9 mg, 32.6% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.70 (s, 1H), 9.05 (s, 1H), 8.26 (s, 1H), 8.22 (t, J = 7.2 Hz, 2H), 7.80 (s, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.39-7.38 (m, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 4.02-3.93 (m, 2H), 3.91-3.89 (m, 2H), 3.77 (s, 2H), 2.84 (d, J = 4.0 Hz, 3H), 2.45-2.30 (m, 7H), 2.28-2.20 (m, 3H) 2.07 (s, 3H), 0.98 (t, J = 7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 606.3.

Example 159: 4 - Cyano -N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)picolinamide (compound 159) manufacturing

[0975] Step 1: Synthesis of 4-cyano-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide

[0976] 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (200 mg, 0.65 mmol), 4-cyanopicolinic acid (120 mg, 0.78 mmol), DIEA (151 mg, 1.17 mmol) in DMF (10.0 mL) ) and HATU (321 mg, 0.85 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20.0 mL) and extracted with EA (50 mL x 2). The combined organic phases were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative-HPLC (0.1% NH3H2O) to afford 4-cyano-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide (100 mg, 35% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.71 (s, 1H), 8.98 (d, J = 4.8 Hz, 1H), 8.46 (s, 1H), 8.25 (br, 1H), 8.15 (dd, J = 4.8, 1.2 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.75 (dd, J = 8.0, 2.0 Hz, 1H), 7.51-7.45 (m, 1H), 7.24-7.18 (m, 2H), 4.10-3.89 (m, 4H), 2.81 (s, 3H), 2.20 (s, 3H). LCMS (M+H ⁺ ) m/z: 437.5.

Example 160:5 - Chloro -N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)nicotinamide (compound 160) manufacturing

[0977] Step 1: Synthesis of N-(3-bromo-4-methylphenyl)-5-chloronicotinamide

[0978] A mixture of 5-chloronicotinic acid (1 g, 6.36 mmol), 3-bromo-4-methylaniline (1.2 g, 6.4 mmol), HATU (2.7 g, 7.7 mmol) and DIEA (1.23 g, 9.54 mmol) in DMF (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (80 mL) and extracted with EA (100 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA = 10/1) to give N-(3-bromo-4-methylphenyl)-5-chloronicotinamide (1.5 g, 47% yield).

[0979] Step 2: Synthesis of 5-chloro-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)nicotinamide

[0980] 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (280 mg, 1.2 mmol), KOAc (650 mg, 6.6 mmol), P d(dppf)Cl2 (160 mg, 0.22 mmol) was added. The mixture was degassed and charged with Ar three times, then stirred at 100 W for 3 hours. The reaction mixture was concentrated in vacuo and H2O (50 mL) was added. The reaction mixture was extracted with EA (100 mL x 3). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE/EA = 10/1) to give 5-chloro-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)nicotinamide (300 mg, 81% yield). LCMS (M+H+) m/z: 373.0.

[0981] Step 3: Synthesis of 5-chloro-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)nicotinamide

[0982] 디옥산 (15.0 mL) 및 물 (3 mL) 중 6-브로모-N-메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (100 mg, 0.36 mmol), 5-클로로-N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)니코틴아미드 (200 mg, 0.54 mmol), Cs ₂ CO ₃ (235 mg, 0.72 mmol) 및 Pd(dppf)Cl ₂ (58 mg, 0.07 mmol)의 혼합물을 탈기하고, N ₂ 로 3회 충전한 다음 100℃에서 16 h 교반하였다. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% HCl) to afford 5-chloro-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)nicotinamide (10 mg, 5% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.90 (s, 1H), 9.77 (s, 1H), 9.09 (s, 1H), 8.98-8.84 (m, 2H), 8.53-8.50 (m, 2H), 8.14 (s, 1H), 7.89 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 4.67-4.54 (m, 2H), 4.10-4.05 (m, 2H), 2.96 (s, 3H), 2.20 (s, 3H). LCMS (M+H ⁺ ) m/z: 446.1.

Example 161:3 -(2- cyanopropane -2-day)-N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)benzamide (Compound 161)

[0983] Step 1: Synthesis of 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide

[0984] 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (90 mg, 0.29 mmol), 3-(2-cyanopropan-2-yl)benzoic acid (55 mg, 0.29 mmol), HATU (168 mg, 0.48 mmol) and DIEA (114 mg, 0.88 mmol) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (50 mL*3). The combined organic phases were washed with brine (50 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% FA) to afford 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide (13.4 mg, 9.6% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.28 (s, 1 H), 8.27 (s, 1 H), 8.19 (s, 1 H), 8.05 (s, 1 H), 7.95 (d, J=7.6 Hz, 1 H), 7.76 (d, J=7.6 Hz, 1 H), 7.69 (d, J=8.4 Hz, 1 H), 7.58-7.64 (m, 2 H), 7.44-7.53 (m, 1 H), 7.22-7.25 (m, 2 H), 4.02-4.11 (m, 2 H), 3.90-3.95 (m, 2 H), 2.86 (s, 3 H), 2.20 (s, 3 H), 1.76 (s, 6 H). LCMS (M+H ⁺ ) m/z: 478.3.

Example 162:2 -(2- cyanopropane -2-day)-N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)isonicotinamide (compound 162) manufacturing

[0985] Step 1: Synthesis of 2-methyl-2-(4-methylpyridin-2-yl)propanenitrile

[0986] To a solution of 2-fluoro-4-methylpyridine (1.11 g, 10 mmol) in toluene (10 mL) was added isobutyronitrile (1.38 g, 20 mmol) and KHMDS (1M in toluene) (20 mL). The mixture was stirred at 110 °C for 1 hour. LCMC results indicated that the reaction was complete. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated to give 2-methyl-2-(4-methylpyridin-2-yl)propanenitrile (630 mg, 40% yield). LCMS (M+H ⁺ ) m/z: 161.0.

[0987] Step 2: Synthesis of 2-(2-cyanopropan-2-yl)isonicotinic acid

[0988] To a solution of 2-methyl-2-(4-methylpyridin-2-yl)propanenitrile (320 mg, 2 mmol) in water (5 mL) was added KMnO4 (632 mg, 4 mmol). The mixture was stirred at 90 °C for 3 hours. LCMC results indicated that the reaction was complete. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated to give 2-(2-cyanopropan-2-yl)isonicotinic acid (180 mg, 47% yield). LCMS (M+H ⁺ ) m/z: 191.0.

[0989] Step 3: Synthesis of 2-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)isonicotinamide

[0990] 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (64 mg, 0.21 mmol), DIEA (8 1 mg, 0.63 mmol) and HATU (118 mg, 0.31 mmol) were added. The mixture was stirred at 25 °C for 2 hours. LCMC results indicated that the reaction was complete. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated to give a crude solid which was purified by preparative-HPLC to yield 2-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl) Acquired sonicotinamide (3.8 mg, 4% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 8.80 (d, J = 5.2 Hz, 1H), 8.30-8.21 (m, 1H), 8.01 (s, 1H), 7.86 (d, J = 5.2 Hz, 1H), 7.67 (dd, J = 8.4, 2.4 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.43 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.10 (s, 1H), 4.04-3.88 (m, 4H), 2.84 (s, 3H), 2.20 (s, 3H), 1.77 (s, 6H). LCMS (M+H+) m/z: 479.0.

Example 163:4 -(2- cyanopropane -2-day)-N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)picolinamide (Compound 163)

[0991] Step 1: Synthesis of 4-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide

[0992] 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (80 mg, 0.26 mmol), 4-(2-cyanopropan-2-yl)picolinic acid (50 mg, 0.26 mmol), HATU (150 mg, 0.39 mmol) and DIEA (101 mg, 0.78 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL), filtered and then the filter cake was purified by column chromatography (DCM: MeOH=20:1) to obtain 4-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide (68. 9 mg, 55.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.97 (s, 1H), 8.88 (s, 1H), 8.81 (d, J = 5.2 Hz, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.12 (m, J = 2.4 Hz, 1H) ), 7.94-7.90 (m, 2H), 7.85-7.83 (m, 1H), 7.42 (d, J = 8.8 Hz, 1H), 4.69-4.56 (m, 2H), 4.06-4.01 (m, 2H), 2.97 (s, 3H), 2.21 (s, 3H), 1 .76 (s, 6H). LCMS (M+H ⁺ ) m/z: 479.3.

Example 164 N-(3-(2-(azetidin-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(2-cyanopropan-2-yl)picolinamide (compound 164) manufacturing

[0993] Step 1: Synthesis of tert-butyl 3-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1-carboxylate

[0994] Dry THF (5 mL) tert-butyl 3-amino jetidine-1-carboxylate (165 mg 0.96 mmol), 6-bromo-2- (methyl sulfinyl) -8,9-dihydro dazza [1 ', 2': 1,6] Flute [2, 3-d] pyrimidine (150 mg, 0.48 mmo L) mixture was stirred at 40 ° C. for 6 hours. The reaction mixture was concentrated in vacuo and then purified by column chromatography on silica gel (DCM/MeOH=15/1) to afford tert-butyl 3-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1-carboxylate (150 mg, 96.5% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 421.1 and 423.1.

[0995] Step 2: Synthesis of tert-butyl 3-((6-(5-amino-2-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1-carboxylate

[0996] 디옥산 (5 mL) 및 물 (0.5 mL) 중 tert-부틸 3-((6-(5-아미노-2-메틸페닐)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)아미노)아제티딘-1-카르복실레이트 (150 mg, 0.356 mmol), 4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)아닐린 (91 mg, 0.392 mmol), Cs ₂ CO ₃ (348 mg, 1.069 mmol) 및 Pd(dppf)Cl ₂ (14 mg, 0.02 mmol)의 혼합물을 탈기하고, N ₂ 로 3회 충전한 다음 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel chromatography (DCM/MeOH=10/1) to afford tert-butyl 3-((6-(5-amino-2-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1-carboxylate (120 mg, 75.4% yield) as a yellow solid. was obtained as LCMS (M+H ⁺ ) m/z: 448.3.

[0997] Step 3: Synthesis of tert-butyl 3-((6-(5-(4-(2-cyanopropan-2-yl)picolinamido)-2-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1-carboxylate

( 37 mg, 0.196 mmol) and HATU (136 mg, 0.357 mmol) was added DIEA (46 mg, 0.357 mmol). The resulting mixture was stirred at room temperature for 2 hours under N ₂ . The reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (DCM/MeOH=10/1) to give tert-butyl 3-((6-(5-(4-(2-cyanopropan-2-yl)picolinamido)-2-methylphenyl)-8,9-dihydroimidazo[1',2':1,6 Obtained ]pyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1-carboxylate (100 mg, 77.7% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 620.9.

[0999] Step 4: Synthesis of N-(3-(2-(azetidin-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(2-cyanopropan-2-yl)picolinamide

[1000] tert-butyl 3-((6-(5-(4-(2-cyanopropan-2-yl)picolinamido)-2-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1-carboxylate (40 mg, 0.065 mmol) was stirred at room temperature for 1 hour. The pH was then adjusted to 8-9 with NH ₃ -H ₂ O, the reaction mixture was concentrated and purified by preparative-HPLC (0.1% NH ₃ -H ₂ O) to N-(3-(2-(azetidin-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(2-cyanopro Pan-2-yl)picolinamide (30.0 mg, 89.5% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.62 (s, 1H), 8.78 (d, J = 5.2 Hz, 1H), 8.25-8.21 (m, 2H), 8.08-7.97 (m, 1H), 7.74-7.35 (m, 3H), 7.21 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 4.71–4.70 (m, 1H), 4.11–3.80 (m, 4H), 3.63–3.33 (m, 4H), 2.20 (s, 3H), 1.76 (s, 6H). LCMS (M+H ⁺ ) m/z: 520.4.

Example 165: 4-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide (compound 165) manufacturing

[1001] The preparation of 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 139.

[1002] Step 1: 4-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide

[1003] 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (70 mg, 0.22 mmol), 4-(2-cyanopropan-2-yl)picolinic acid (43 mg, 0.22 mmol), HATU (1 A solution of 23 mg, 0.32 mmol) and DIEA (84 mg, 0.65 mmol) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL), filtered and the filter cake was purified by column chromatography on silica gel (DCM: MeOH=20:1) to obtain 4-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picoline The amide (19.0 mg, 55.1% yield) was obtained as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.39 (s, 1 H), 8.82 (d, J=5.6 Hz, 1 H), 8.29-8.25 (m, 2 H), 7.92 (d, J=8.0 Hz, 1 H), 7.88-7.86 (m, 1 H), 7.59-7.4 9 (m, 1 H), 7.27–7.24 (m, 2 H), 4.14–4.03 (m, 2 H), 3.95–3.90 (m, 2 H), 2.86 (s, 3 H), 2.23 (s, 3 H), 1.76 (s, 6 H). LCMS (M+H ⁺ ) m/z: 497.5.

Example 166: 2-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)isonicotinamide (compound 166) manufacturing

[1004] Step 1: Synthesis of 2-(4-bromopyridin-2-yl)-2-methylpropanenitrile

[1005] To a solution of 4-bromo-2-fluoropyridine (500 mg, 2.84 mmol) in toluene (10 mL) was added isobutyronitrile (196 mg, 2.84 mmol) and KHMDS (1.0 M, 2.8 mL, 2.84 mmol). The reaction mixture was stirred for 2 h at 80 °C, quenched with NH ₄ Cl (aq.) (20 mL) then extracted with EA (20 mL x 2). The combined organic phases were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EA=20:1) to give 2-(4-bromopyridin-2-yl)-2-methylpropanenitrile (350 mg, 54.7% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.41 (d, J=4.2 Hz, 1 H), 7.85 (d, J=1.2 Hz, 1 H), 7.70-7.69 (m, 1 H), 1.71 (s, 6 H).

[1006] Step 2: Synthesis of ethyl 2-(2-cyanopropan-2-yl)isonicotinate

[1007] To a solution of 2-(4-bromopyridin-2-yl)-2-methylpropanenitrile (350 mg, 1.56 mmol) in EtOH (6 mL) was added AcOK (457 mg, 4.67 mmol) and Pd(dppf)Cl ₂ (114 mg, 0.16 mmol). The resulting mixture was stirred at 80 °C for 3 h under CO. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EA=10:1) to give ethyl 2-(2-cyanopropan-2-yl)isonicotinate (228 mg, 67.1% yield) as a red solid. LCMS (M+H ⁺ ) m/z: 219.2.

[1008] Step 3: Synthesis of 2-(2-cyanopropan-2-yl)isonicotinic acid

[1009] To a solution of ethyl 2-(2-cyanopropan-2-yl)isonicotinate (280 mg, 1.28 mmol) in MeOH/H ₂ O (5 mL/1 mL) was added LiOH (92 mg, 3.85 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to remove MeOH and extracted with EA. The aqueous phase was brought to pH=2-3 with 1N HCl and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 2-(2-cyanopropan-2-yl)isonicotinic acid (200 mg, 82% yield) as a white solid.

[1010] Step 4: Synthesis of 2-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)isonicotinamide

[1011] 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (80 mg, 0.25 mmol), 2-(2-cyanopropan-2-yl)isonicotinic acid (50 mg, 0.26 mmol), HA in DMF (3 mL) A mixture of TU (140 mg, 0.37 mmol) and DIEA (96 mg, 0.74 mmol) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and filtered. The filter cake was purified by preparative-HPLC (0.1% NH3H2O) to yield 2-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)isonicotinamide (11.3 mg, 9.3% aqueous rate) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.46 (s, 1H), 8.80 (d, J = 4.8 Hz, 1H), 8.23-8.17 (m, 1H), 8.04 (s, 1H), 7.87-7.85 (m, 2H), 7.23 (d, J = 3.2 Hz , 1H), 7.13 (s, 1H), 4.02–4.01 (m, 2H), 3.93–3.88 (m, 2H), 2.84 (d, J = 4.4 Hz, 3H), 2.24 (s, 3H), 1.76 (s, 6H). LCMS (M+H ⁺ ) m/z: 497.3.

Example 167: 3-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide (compound 167) manufacturing

[1012] 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3- The preparation of d]pyrimidin-2-amine is described in Example 139.

[1013] Step 1: Synthesis of 3-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide

[1014] 3-(2-cyanopropan-2-yl)benzoic acid (38 mg, 0.20 mmol), 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (65 mg, 0.20 mmol), and HATU in DMF (5.0 mL) (115 mg, 0.30 mmol) was added DIEA (52 mg, 0.40 mmol). The resulting mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was quenched with water (20 mL) and extracted with DCM (20 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product which was purified by Pre-HPLC (0.1% NH ₃ .H ₂ O) to give 3-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[ Obtained 2,3-d]pyrimidin-6-yl)phenyl)benzamide (18.6 mg, 18.8% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.19 (s, 1H), 8.24-8.22 (m, 1H), 8.08 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.77-7.75 (m, 1H), 7.61-7.57 (m, 1H), 7.45-7.40 (m, 2H), 7.22-7.13 (m, 2H), 4.12-3.99 (m, 2H), 3.91 (t, J = 8.0 Hz, 2H), 2.84 (s, 3H), 2.24 (s, 3H), 1.75 (s, 6H). LCMS (M+H ⁺ ) m/z: 496.2.

Example 168: 3-(2-cyanopropan-2-yl)-N-(5-(2-(dimethylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)benzamide (compound 168) manufacturing

[1015] Step 1: Synthesis of 6-(5-amino-4-fluoro-2-methylphenyl)-N,N-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1016] 6-Bromo-N,N-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (240 mg, 0.815 mmol) in dioxane (12 mL) and H ₂ O (3 mL), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-di To a solution of oxaborolan-2-yl)aniline (307 mg, 1.223 mmol) and Cs ₂ CO ₃ (796 mg, 2.445 mmol) was added Pd(dppf)Cl ₂ (60 mg, 0.082 mmol). The reaction mixture was stirred at 100 °C under N ₂ for 3 hours. The resulting solution was concentrated and purified by flash chromatography to give 6-(5-amino-4-fluoro-2-methylphenyl)-N,N-dimethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (260 mg, 94.2% yield) as a yellow solid.

[1017] Step 2: Synthesis of 3-(2-cyanopropan-2-yl)-N-(5-(2-(dimethylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)benzamide formate

[1018] To a solution of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (100 mg, 0.295 mmol) and 3-(2-cyanopropan-2-yl)benzoic acid (56 mg, 0.295) in DMF (5 mL) was added DIEA (114 mg, 0.886 mmol) and HATU (337 mg, 0.886 mmol) was added. The reaction mixture was stirred at room temperature under N ₂ for 3 hours. H ₂ O (20 mL) was added and the reaction mixture was extracted twice with EA. The pooled extracts were washed with brine (20 mL). Concentrated in vacuo and purified by preparative-TLC (DCM: MeOH=30:1) and preparative-HPLC (0.1%/FA/CH ₃ CN/H ₂ O) to obtain 3-(2-cyanopropan-2-yl)-N-(5-(2-(dimethylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-2- Obtained fluoro-4-methylphenyl)benzamide formate (16.55 mg, 11% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.20 (s, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 8.09 (s,1H), 7.94 (d, J = 7.6 Hz,1H), 7.75 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.40 (d, J =7.6 Hz, 1H), 7.20 (d, J = 12.0 Hz, 1H), 7.14 (s, 1H), 4.05-4.01 (m, 2H), 3.94-3.89 (m, 2H), 2.24 (s, 3H), 1.75 (s, 6H). LCMS (M+H ⁺ ) m/z: 510.2.

Example 170:3 -(2-hydroxypropan-2-yl)-N-(4- methyl -3-(2-( methylamino Preparation of )-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide (Compound 170)

[1019] Step 1: Synthesis of 3-(2-hydroxypropan-2-yl)benzoic acid

[1020] A 2.5 M solution of n-butyllithium (4 mL, 9.95 mmol) in hexane fraction was added dropwise to a solution of 1.0 g (4.97 mmol) of 3-bromobenzoic acid in 20 mL of anhydrous THF at -78°C under argon. After 20 minutes, 730 uL (9.95 mmol) of acetone was added dropwise at the same temperature. The reaction mixture was stirred at -78 °C for an additional hour and then allowed to warm to room temperature over about 1 hour. The reaction mixture was then hydrolyzed by carefully adding several drops of saturated aqueous ammonium chloride solution and AcOH (2.0 mL). The mixture was diluted with 200 mL of water and extracted twice with about 50 mL of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and the solvent removed on a rotary evaporator. The obtained residue was flash purified (PE: EA=3:1). Evaporation to dryness under high vacuum gave 3-(2-hydroxypropan-2-yl)benzoic acid (356 mg, 39% yield). ^1H NMR (400 MHz, CDCl3): 8.23 (s, 1H), 8.02-7.99 (m, 1H), 7.80-7.77 (m, 1H), 7.48-7.46 (m, 1H), 1.63 (s, 6H). LCMS (M-18)-m/z: 163.0.

[1021 Step 2: Synthesis of 3-(2-hydroxypropan-2-yl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide

[1022] 3-(2-hydroxypropan-2-yl)benzoic acid (36 mg, 0.18 mmol), HATU (76 mg, 0.18 mmol), DIPEA (58 mg, 0.45 mmol), 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2, A mixture of 3-d]pyrimidin-2-amine (45 mg, 0.15 mmol) was stirred at 10 °C for 2 h. Water was added and the reaction mixture was extracted with EA. The pooled extracts were washed with brine. The reaction was concentrated and purified by flash (DCM: MeOH=10:1) and then HPLC (0.5% FA) to obtain pure 3-(2-hydroxypropan-2-yl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide (14.1 mg, 20% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 9.71 (s, 1H), 8.87 (s, 1H), 8.53-8.52 (m, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.84-7.66 (m, 3H), 7.46 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 4.67-4.57 (m, 2H), 4.04-3.99 (m, 2H), 2.97-2.95 (d, 3H), 2.18 (s, 3H), 1.47-1.43 (s, 6H). LCMS (M+H+) m/z: 469.0.

Example 171: N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-hydroxypropan-2-yl)benzamide (compound 171) manufacturing

[1023] Step 1: Synthesis of ethyl 3-(2-hydroxypropan-2-yl)benzoate

[1024] 1-((6-chloro-4-(trifluoromethyl)pyridin-3-yl)methyl)-4-ethylpiperazine (100 mg, 0.47 mmol) in EtOH (20 mL), AcOK (182 mg, 1.86 mmol) and Pd(dppf)Cl ₂ (17 mg, 0.02 mmol) was degassed, charged with CO three times and stirred at 80° C. for 16 h under CO. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (PE:EA=4:1) to give ethyl 3-(2-hydroxypropan-2-yl)benzoate (80 mg, 78% yield) as a white solid. LCMS (M-17) m/z: 191.1.

[1025] Step 2: Synthesis of 3-(2-hydroxypropan-2-yl)benzoic acid

[1026] LiOH (69 mg, 2.88 mmol) was added to a mixture of ethyl ethyl 3-(2-hydroxypropan-2-yl)benzoate (100 mg, 0.29 mmol) in THF:H ₂ O (5:1) (5 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with DCM (20 mL). The aqueous phase was adjusted to pH=3 with 2N HCl and then concentrated to give 3-(2-hydroxypropan-2-yl)benzoic acid (80 mg, crude) as a white solid. LCMS (MH)-m/z: 179.1.

[1027] Step 3: Synthesis of 5-((4-ethylpiperazin-1-yl)methyl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[1028] 3-(2-hydroxypropan-2-yl)benzoic acid (50 mg, 0.28 mmol), 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (90 mg, 0.28 mmol) in DMF (2 mL), DIEA (25 mg, 0.20 mmol) was added HATU (211 mg, 0.56 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mLx3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated to give the crude product which was purified by preparative-HPLC (0.1% NH3.H2O) to give 5-((4-ethylpiperazin-1-yl)methyl)-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2, Obtained 3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (14.8 mg, 10.9% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.06 (s, 1H), 8.24-8.19 (m, 1H), 8.07 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.47-7.38 (m, 3H), 7.20-7.14 (m, 2H), 5.15 (s, 1H), 4.04-3.96 (m, 2H), 3.91 (t, J = 8.0 Hz, 2H), 2.85 (m, 3H), 2.20 (s, 3H), 1.47 (s, 6H). LCMS (M+H ⁺ ) m/z : 487.2

Example 172:6 -(2,4- dichlorophenyl )-N-(3- Fluoro -4-(4- Methylpiperazine Preparation of -1-yl)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (Compound 172)

[1029] Step 1: Synthesis of 2-(2-chloropyridin-4-yl)propan-2-ol

[1030] To a solution of 2-chloro-4-iodopyridine (1.0 g, 4.18 mmol) in THF (15 mL) was added n-BuLi (1.6 M, 2.6 mL, 4.18 mmol) at -78 ^° C. After 15 min, acetone (728 mg, 12.55 mmol) was added. The reaction mixture was stirred at -78 °C for 2 h, quenched with NH ₄ Cl (aq.) (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were washed with brine (20 mL), then dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EA=5:1) to give 2-(2-chloropyridin-4-yl)propan-2-ol (490 mg, 68.5% yield) as a yellow oil. LCMS (M+H ⁺ ) m/z: 172.1.

[1031] Step 2: Synthesis of ethyl 4-(2-hydroxypropan-2-yl)picolinate

[1032] To a solution of 2-(2-chloropyridin-4-yl)propan-2-ol (49 mg, 2.87 mmol) in EtOH (10 mL) was added AcOK (842 mg, 8.60 mmol) and Pd(dppf)Cl ₂ (210 mg, 0.29 mmol). The resulting mixture was stirred at 80 °C for 3 h under CO. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EA=2:1) to give ethyl 4-(2-hydroxypropan-2-yl)picolinate (400 mg, 63% yield) as a red oil. LCMS (M+H ⁺ ) m/z: 210.2.

[1033] Step 3: Synthesis of 4-(2-hydroxypropan-2-yl)picolinic acid

[1034] LiOH (138 mg, 5.74 mmol) to a solution of ethyl 4-(2-hydroxypropan-2-yl)picolinate (400 mg, 1.91 mmol) in MeOH/ _H 2 O (10 mL/2 mL) ) was added. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated to remove MeOH and extracted with EA. The aqueous phase was adjusted to pH=2-3 with 1N HCl and concentrated in vacuo to give 4-(2-hydroxypropan-2-yl)picolinic acid (1.0 g, crude) as a yellow oil. LCMS (M+H ⁺ ) m/z: 182.1.

[1035] Step 4: Synthesis of N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(2-hydroxypropan-2-yl)picolinamide

[1036] 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (80 mg, 0.25 mmol), 4-(2-hydroxypropan-2-yl)picolinic acid (268 mg, 0.19 mmol), HATU ( A mixture of 141 mg, 0.37 mmol) and DIEA (95 mg, 0.74 mmol) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by Pre-HPLC (0.1% NH ₃ H ₂ O) to afford N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(2-hydroxypropan-2-yl)picolinamide (36 mg, 30% yield) as a yellow solid. . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.35 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 8.25-8.19 (m, 2H), 7.96 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 4.4, 1.6 Hz, 1H), 7.42-7.41 (m, 1H), 7.25 (d, J = 11.6 Hz, 1H), 7.14 (s, 1H), 5.47 (s, 1H), 4.05-3.99 (m, 2H), 3.93-3.88 (m, 2H), 2.85 (d, J = 4.0 Hz, 3H), 2.22 (s, 3H), 1.46 (s, 6H). LCMS (M+H ⁺ ) m/z: 488.3.

Example 173: 3-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide (compound 173) manufacturing

[1037] The preparation of 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 141.

[1038] Step 1: Synthesis of 3-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide

[1039] 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.15 mmol, 1.0 eq) and 3-(2-cyanopropan-2-yl)benzoic acid (43 mg, 0.23 mmol) in DMF (3 mL) , and 1.5 eq) was added DIEA (0.1 mL) and HATU (88 mg, 0.23 mmol, 1.5 eq). The mixture was stirred overnight at 20 °C. LCMS results indicated that the reaction performed well. Water was added and the reaction mixture was extracted with EA. The pooled extracts were washed with brine. Concentrated and then purified by preparative-HPLC (0.1% NH ₄ OH) to give 3-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide (4.8 mg, 6.5 % yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.57-8.51 (m, 2H), 8.11 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 4.59-4.48 (m, 2H), 4.11-4.05 (m, 2H), 3.04 (s, 3H), 2.29 (s, 3H), 1.78 (s, 6H). LCMS (M+H ⁺ ) m/z: 496.1.

Example 174: 4-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide (compound 174) manufacturing

[1040] Step 1: Synthesis of 4-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide

[1041] 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.15 mmol, 1.0 eq) and 4-(2-cyanopropan-2-yl)picolinic acid in DMF (3 mL) (45 mg, 0.23 mmol, and 1.5 eq) was added DIEA (0.1 mL) and HATU (88 mg, 0.23 mmol, 1.5 eq). The mixture was stirred overnight at 20 °C. LCMS results indicated that the reaction performed well. Water was added and the reaction mixture was extracted with EA. The pooled extracts were washed with brine. Concentration and purification by prep-HPLC (0.1% HCl) afforded 4-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide (8.6 mg, 11.6% yield) as a yellow solid. . ^1H NMR (400 MHz, CD ₃ OD): δ 8.86 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.41 (s, 1H), 8.24 (t, J = 8.0 Hz, 1H), 8.17 (s, 1H), 7.84-7.82 (m, 1H), 7 .31 (d, J = 8.4 Hz, 1H), 4.86–4.79 (m, 2H), 4.20–4.15 (m, 2H), 3.10 (s, 3H), 2.30 (s, 3H), 1.81 (s, 6H). LCMS (M+H ⁺ ) m/z: 497.1.

Example 175: isopropyl (6-(5-(4-(2-cyanopropan-2-yl)picolinamido)-4-fluoro-2-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)carbamate (compound 175) manufacturing

[1042] Step 1: Synthesis of isopropyl (6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)carbamate

[1043] To a solution of 6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (300 mg, 1.28 mmol) in THF (15.0 mL) was added NaH (90 mg, 2.26 mmol) at 0°C, the mixture was stirred for 1 hour, then isopropyl carbonochloridate (379 mg, 3.38 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was concentrated in vacuo and then purified by column chromatography on silica gel (DCM/MeOH=10/1) to give isopropyl (6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)carbamate (90 mg, 20% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 352.2 and 354.2.

[1044] Step 2: Synthesis of isopropyl (6-(5-amino-4-fluoro-2-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)carbamate

[1045] Isopropyl (6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)carbamate (25 mg, 0.071 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-di in dioxane (5 mL) and H ₂ O (0.5 mL) Oxaborolan-2-yl)aniline (22 mg, 0.085 mmol), Cs ₂ CO ₃ (69 mg, 0.213 mmol), and Pd(dppf)Cl ₂ (5 mg, 0.007 mmol) was degassed, charged 3 times with N ₂ and stirred at 90° C. for 16 h under N ₂ . The reaction mixture was concentrated in vacuo and then purified by column chromatography on silica gel (DCM/MeOH=15/1) to give isopropyl (6-(5-amino-4-fluoro-2-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)carbamate (23 mg, 81.8% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 397.3.

[1046] Step 3: Synthesis of isopropyl (6-(5-(4-(2-cyanopropan-2-yl)picolinamido)-4-fluoro-2-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)carbamate formic acid salt

[1047] 4-(2-cyanopropan-2-yl)picolinic acid (14 mg, 0.07mmol), isopropyl (6-(5-amino-4-fluoro-2-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)carbamate (23 mg, 0.065 mmol), and HATU (50 mg, 0.13 mmol) was added DIEA (25 mg, 0.196 mmol). The resulting mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was quenched with water (20 mL) and extracted with DCM (20 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO4, filtered, and concentrated to give the crude product, which was purified by preparative-HPLC (0.1% FA) to give isopropyl (6-(5-(4-(2-cyanopropan-2-yl)picolinamido)-4-fluoro-2-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2 ,3-d]pyrimidin-2-yl)carbamate formic acid salt (6.4 mg, 16.1% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.42 (s, 1H), 10.25 (s, 1H), 8.82 (d, J = 5.2 Hz, 1H), 8.43 (s, 1H), 8.26 (s, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 6.0, 2.0 Hz, 1H), 7.28 (t, J = 4.4 Hz, 2H), 4.94-4.87 (m, 1H), 4.06 (t, J = 8.4 Hz, 2H), 3.95 (t, J = 8.4 Hz, 2H), 2.25 (s, 3H), 1.76 (s, 6H), 1.27 (s, 3H), 1.25 (s, 3H). LCMS (M+H ⁺ ) m/z: 569.6.

Example 176: isopropyl (6- (4-fluoro-2-methyl-5- (4- (trifluoromethyl) picolinamido) phenyl) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-yl) carbamate (compound 176) manufacturing

[1048] Step 1: Synthesis of isopropyl (6-(4-fluoro-2-methyl-5-(4-(trifluoromethyl)picolinamido)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)carbamate formic acid salt

[1049] 디옥산 (5 mL) 및 H ₂ O (0.5 mL) 중 이소프로필 (6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)카바메이트 (30 mg, 0.085 mmol), N-(2-플루오로-4-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린아미드 (43 mg, 0.102 mmol), Cs ₂ CO ₃ (83 mg, 0.256 mmol), 및 Pd(dppf)Cl _{2 (} 6 mg, 0.008 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전한 다음 90℃에서 16 시간 동안 N ₂ 하에 교반하였다. The reaction mixture was concentrated in vacuo and then purified by column chromatography on silica gel (DCM/MeOH=10/1) to give the crude product which was purified by preparative-HPLC (0.1% FA) to isopropyl (6-(4-fluoro-2-methyl-5-(4-(trifluoromethyl)picolinamido)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine. -2-yl)carbamate formic acid salt (10.8 mg, 20.7% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.48 (s, 1H), 10.24 (s, 1H), 9.06 (d, J = 5.2 Hz, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.14 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 6.4 Hz, 2H), 4.94-4.87 (m, 1H), 4.06 (t, J = 8.4 Hz, 2H), 3.95 (t, J = 8.4 Hz, 2H), 2.26 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H). LCMS (M+H ⁺ ) m/z: 570.5.

Example 177: N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 177) manufacturing

[1050] Step 1: Synthesis of 3-fluoro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide

[1051] To a solution of 3-(trifluoromethyl)benzoic acid (60 mg, 0.316 mmol) and DMF (1.2 uL, 0.016 mmol) in dry DCM (6 mL) was added oxalyl chloride (48 mg, 0.379 mmol) dropwise under N ₂ at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and dissolved in dry DMF (3 mL), then DIEA (86 mg, 0.670 mmol) and 6-(5-amino-4-fluoro-2-methylphenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (123 mg, 0.335 mmol) in DMF (1 mL) ) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H ₂ O (20 mL), extracted with DCM (30 mL x 3), dried over Na2SO4, and filtered. The combined organic layers were concentrated in vacuo and then purified by column chromatography on silica gel (DCM/MeOH=15/1) to give the crude product which was purified by preparative-HPLC (0.1% NH ₃ -H ₂ O) to obtain 3-fluoro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6 Obtained ]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide (27.7 mg, 16.3% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.37 (s, 1H), 8.31 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.22-8.21 (m, 2H), 7.98 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 11.6 Hz, 1H), 7.14 (s, 1H), 4.95-4.92 (m, 1H), 4.76 (t, J = 6.4 Hz, 2H), 4.54 (t, J = 6.4 Hz, 2H), 4.03-3.88 (m, 4H), 2.23 (s, 3H). LCMS (M+H+) m/z: 539.2.

Example 178: N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (compound 178) manufacturing

[1052] The preparation of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine is described in Example 26.

[1053] Step 1: Synthesis of 2-fluoro-4-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline

[1054] 5-Bromo-2-fluoro-4-methylaniline (6.0 g, 29.4 mmol), bis(pinacolato)diboron (8.96 g, 35.3 mmol), AcOK (8.6 g, 88.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.07 g, 1.47 mmol) of the mixture. The obtained mixture was degassed, charged with N ₂ three times, and then stirred at 100° C. for 16 hours. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EA=5:1) to give 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.1 g, 96% yield) as an off-white solid. LCMS (M+H ⁺ ) m/z: 252.0.

[1055] Step 2: 6-Bromo-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] Synthesis of pyrimidin-2-amines

[1057] A mixture of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (1.9 g, 6.07 mmol), oxetan-3-amine (2.2 g, 30.35 mmol), DIEA (1.57 g, 12.14 mmol) in THF (40.0 mL). The resulting mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated. The residue was triturated with EA (10.0 mL) to give crude 6-bromo-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (2.0 g, 100% yield) as a yellow solid which was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 321.9 and 323.9.

[1057] Step 3: Synthesis of 6-(5-amino-4-fluoro-2-methylphenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1058] 디옥산 (40.0 mL) 및 H ₂ O (4.0 mL) 중 6-브로모-N-(옥세탄-3-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (1.8 g, 5.59 mmol), 2-플루오로-4-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)아닐린 (1.47 g, 5.87 mmol), Cs ₂ CO ₃ (3.64 g, 11.18 mmol) 및 [1,1'-비스(디페닐포스피노)페로센]디클로로팔라듐(II) (204 mg, 0.28 mmol)의 혼합물을 100℃에서 16 시간 동안 N ₂ 하에 교반하였다. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH=20:1) and then triturated with PE/EA (1:1, 10.0 mL) to give 6-(5-amino-4-fluoro-2-methylphenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (1.21 g, 5 9% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 367.1.

[1059] Step 4: N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1, Synthesis of 6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide

[1060] 4-(trifluoromethyl)picolinic acid (365 mg, 1.91 mmol), 6-(5-amino-4-fluoro-2-methylphenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (700 mg, 1.91 mmol) and HATU (1.45 g, 3.82 mmol) was added DIEA (493 mg, 3.82 mmol). The resulting mixture was stirred at room temperature for 2.5 hours under N ₂ . The reaction mixture was added slowly to water (45 mL), stirred at room temperature for 30 minutes and filtered. The collected cake was purified by silica column chromatography (DCM:MeOH=15:1, +0.2% NH ₃ -MeOH) to obtain N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinamide (606. 4 mg, 52% yield) as a yellow solid. ¹ H NMR (400 MHz, CD3OD): δ 8.97 (d, J = 5.2 Hz, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 4.8 Hz, 1H), 7.41 (s, 1H), 7.20 (d, J = 11.6 Hz, 1H), 5.13 (t, J = 6.8 Hz, 1H), 4.96 (t, J = 6.8 Hz, 2H), 4.71-4.70 (m, 2H), 4.31 (t, J = 9.6 Hz, 2H), 4.03 (t, J = 10.0 Hz, 2H), 2.26 (s, 3H). LCMS (M+H ⁺ ) m/z: 540.6.

Example 179: N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-6-(trifluoromethyl)picolinamide (compound 179) manufacturing

[1061] Step 1: Synthesis of N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-6-(trifluoromethyl)picolinamide

[1062] 6-(5-amino-4-fluoro-2-methylphenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.14 mmol), 6-(trifluoromethyl)picolinic acid (31 mg, 0.16 mmol) in DMF (2 mL), DIEA (54.2 mg, 0.42 mmol) was added HATU (77.8 mg, 0.20 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL) and filtered. The solid was washed with water (30 mL) and purified by column chromatography on silica gel (DCM:MeOH=10:1) to give the crude product which was triturated with MeOH (20 mL) to N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-6 Obtained -(trifluoromethyl)picolinamide (20.2 mg, 27.4% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.23 (s, 1H), 8.41-8.36 (m, 2H), 8.25-8.19 (m, 4H), 7.84 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 12.0 Hz, 1H), 7.16 (s, 1H), 4.95-4.92 (m, 1H), 4.77 (t, J = 6.0 Hz, 2H), 4.54 (t, J = 6.4 Hz, 2H), 4.04-3.99 (m, 2H), 3.94-3.89 (m, 2H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 540.2.

Example 180: 3-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide (compound 180) manufacturing

[1063] Step 1: Synthesis of 3-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide

[1064] HATU (77.8 mg, 0.20 mmol) was added to 6-(5-amino-4-fluoro-2-methylphenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.14 mmol), 3-(2-cyanopropane) in DMF (2 mL) -2-yl)benzoic acid (31 mg, 0.16 mmol) and DIEA (54.2 mg, 0.42 mmol) were added to a mixture. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and filtered. The obtained solid was purified by preparative-HPLC (0.1% NH ₃ .H ₂ O) to obtain 3-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzamide (12.8 mg, 17.5% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.20 (s, 1H), 8.22 (d, J = 4.8 Hz, 2H), 8.09 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 11.2 Hz, 1H), 7.14 (s, 1H), 4.95-4.92 (m, 1H), 4.77 (t, J = 6.4 Hz, 2H), 4.54 (t, J = 6.4 Hz, 2H), 4.01 (t, J = 8.8 Hz, 2H), 3.94-3.89 (m, 2H), 2.24 (s, 3H), 1.75 (s, 6H). LCMS (M+H ⁺ ) m/z: 538.2.

Example 181: 4-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide (compound 181) manufacturing

[1065] Step 1: Synthesis of 2-(2-bromopyridin-4-yl)-2-methylpropanenitrile

[1066] To a solution of 2-bromo-4-fluoropyridine (2.0 g, 11.36 mmol) in toluene (20 mL) was added isobutyronitrile (784 mg, 1.00 mmol) and KHMDS (1.0 M, 11.4 mL, 11.36 mmol). The reaction mixture was stirred for 2 h at 80 °C, quenched with NH ₄ Cl (aq.) (30 mL) then extracted with EA (30 mL x 2). The combined organic phases were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA=50:1) to give 2-(2-bromopyridin-4-yl)-2-methylpropanenitrile (1.2 g, 47.1% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.41 (d, J=5.2 Hz, 1 H), 7.59 (d, J=1.2 Hz, 1 H), 7.37-7.37 (m, 1 H), 1.74 (s, 6 H).

[1067] Step 2: Synthesis of ethyl 4-(2-cyanopropan-2-yl)picolinate

[1068] To a solution of 2-(2-bromopyridin-4-yl)-2-methylpropanenitrile (1.2 g, 5.33 mmol) in EtOH (20 mL) was added AcOK (1.6 g, 16.00 mmol) and Pd(dppf)Cl ₂ (390 mg, 0.53 mmol). The resulting mixture was stirred at 80° C. for 3 h under CO. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA=3:1) to give ethyl 4-(2-cyanopropan-2-yl)picolinate (900 mg, 74.3% yield) as a red solid. LCMS (M+H ⁺ ) m/z: 219.1.

[1069] Step 3: Synthesis of 4-(2-cyanopropan-2-yl)picolinic acid

[1070] To a solution of ethyl 4-(2-cyanopropan-2-yl)picolinate (900 mg, 4.13 mmol) in MeOH/H ₂ O (10 mL/2 mL) was added LiOH (297 mg, 12.39 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated to remove MeOH and extracted with EA. The aqueous phase was adjusted to pH=2-3 with 1N HCl and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 4-(2-cyanopropan-2-yl)picolinic acid (190 mg, 88.8% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 191.2.

[1071] Step 4: Synthesis of 4-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide

[1072] 6-(5-amino-4-fluoro-2-methylphenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (80 mg, 0.22 mmol), 4-(2-cyanopropan-2-yl)picolinic acid (42 mg, 0.2 2 mmol), HATU (125 mg, 0.33 mmol) and DIEA (85 mg, 0.66 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and filtered. The filter cake was purified by column chromatography (DCM: MeOH=20:1) to obtain 4-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide (25 mg, 21.4% aqueous rate) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.46 (s, 1H), 8.87 (d, J = 5.2 Hz, 1H), 8.35-8.31 (m, 3H), 7.97-7.92 (m, 2H), 7.33-7.30 (m, 2H), 5.01 (s, 1 H), 4.85-4.82 (m, 2H), 4.62-4.59 (m, 2H), 4.12-4.08 (m, 2H), 4.01-3.96 (m, 2H), 2.28 (s, 3H), 1.82 (s, 6H). LCMS (M+H ⁺ ) m/z: 539.2.

Example 182: 6-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide (compound 182) manufacturing

[1073] Step 1: Synthesis of 2-(6-bromopyridin-2-yl)-2-methylpropanenitrile

[1074] To a solution of 2-bromo-6-fluoropyridine (176 mg, 1.00 mmol) in toluene (5 mL) was added isobutyronitrile (69 mg, 1.00 mmol) and KHMDS (1.0 M, 1.0 mL, 1.00 mmol). The reaction mixture was stirred at 80 °C for 2 h, then quenched with NH ₄ Cl (aq.) (10 mL) and extracted with EA (10 mL x 2). The combined organic phases were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative-TLC (PE: EA=2:1) to give 2-(6-bromopyridin-2-yl)-2-methylpropanenitrile (100 mg, 44.4% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.61-7.56 (m, 2 H), 7.44-7.42 (m, 1 H), 1.75 (s, 6 H).

[1075] Step 2: Synthesis of ethyl 6-(2-cyanopropan-2-yl)picolinate

[1076] To a solution of 2-(6-bromopyridin-2-yl)-2-methylpropanenitrile (160 mg, 0.71 mmol) in EtOH (10 mL) was added AcOK (209 mg, 2.13 mmol) and Pd(dppf)Cl ₂ (52 mg, 0.071 mmol). The resulting mixture was stirred at 80° C. for 3 h under CO. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA=10:1) to give ethyl 6-(2-cyanopropan-2-yl)picolinate (135 mg, 87.3% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 219.2.

[1077] Step 3: Synthesis of 6-(2-cyanopropan-2-yl)picolinic acid

[1078] To a solution of ethyl 6-(2-cyanopropan-2-yl)picolinate (220 mg, 1.01 mmol) in MeOH/H ₂ O (10 mL/2 mL) was added LiOH (72 mg, 3.03 mmol). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated to remove MeOH and extracted with EA. The aqueous phase was adjusted to pH=2-3 with 1N HCl and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 6-(2-cyanopropan-2-yl)picolinic acid (190 mg, 88.8% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 191.1.

[1079] Step 4: Synthesis of 6-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide

[1080] 6-(5-amino-4-fluoro-2-methylphenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (70 mg, 0.19 mmol), 6-(2-cyanopropan-2-yl)picolinic acid (36 mg, 0.1 9 mmol), HATU (109 mg, 0.29 mmol) and DIEA (74 mg, 0.57 mmol) were stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and filtered. The filter cake was triturated with MeOH (5 mL) and filtered. The solid was dried to give 6-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinamide (19.3 mg, 18.9% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.33 (s, 1H), 8.24-8.16 (m, 3H), 8.13 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 11.6 Hz, 1H), 7.17 (s, 1H), 4.95 (br, 1H), 4.77 (s, 2H), 4.55 (m, 2H), 4.02 (t, J = 9.6 Hz, 2H), 3.94 (J = 8.4 Hz, 2H), 2.23 (s, 3H), 1.82 (s, 6H). LCMS (M+H ⁺ ) m/z: 539.2.

Example 183: N-(4-chloro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-cyanopropan-2-yl)benzsulfonamide (compound 183) manufacturing

[1081] Step 1: Synthesis of 6-(5-amino-2-chlorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo [1', 2': 1, 6] pyrido [2, 3-d] pyrimidin-2-amine

[1082] 디옥산/H ₂ O (25/5 mL) 중 6-브로모-N-(옥세탄-3-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (500 mg, 1.56 mmol, 1.0 eq) 및 4-클로로-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)아닐린 (512 mg, 2.02 mmol, 1.3 eq)의 혼합물에 Pd(G) ₃ (132 mg, 0.156 mmol, 0.1 eq) 및 Cs ₂ CO ₃ (1.5 g, 4.68 mmol, 3.0 eq), Ru-phos (73 mg, 0.156 mmol, 0.1 eq)를 첨가하였다. The mixture was stirred at 100 °C under N ₂ for 16 h. Concentration in vacuo and purification on silica gel column chromatography (DCM/MeOH = 10: 1) gave 6-(5-amino-2-chlorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo [1', 2': 1, 6] pyrido [2, 3-d] pyrimidin-2-amine (320 mg, 55.7% yield) as a yellow solid.

[1083] Step 2: Synthesis of N-(4-chloro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-cyanopropan-2-yl)benzsulfonamide

[1084] 6-(5-amino-2-chlorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60.0 mg, 0.16 mmol, 1.0 eq), 3-(2-cyanopropan-2-yl)benzoic acid (30.0 mg) in DMF (5 mL) , 0.16 mmol, 1.0 eq) was added HATU (121.6 mg, 0.32 mmol, 2.0 eq) and DIEA (41.3 mg, 0.32 mmol, 3.0 eq). The mixture was stirred at room temperature under N ₂ for 16 h. H ₂ O (20 mL) was added and the reaction mixture was extracted twice with EA. The pooled extracts were washed with brine (20 mL). Concentrated in vacuo and purified by preparative-HPLC (0.1% NH ₄ HCO ₃ ) to N-(4-chloro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-cyanopropan-2-yl)benzsulfonamide (5.0 mg, 12% yield) ) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.46 (s, 1H), 8.27 (d, J= 5.6 Hz, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.84-7.75 (m, 3H), 7.61 (t, J=7.6 Hz,1H), 7.50 (d, J=8.4 Hz, 1H), 7.23 (s, 1H), 4.96 (br s, 1H), 4.77-4.76 (m, 2H), 4.56-4.53 (m, 2H), 4.01-3.99 (m, 2H), 3.93-3.91 (m, 2H, 1.73 (s, 6H). LCMS (M+H ⁺ ) m/z: 540.1.

Example 184: Preparation of N-(4-chloro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(2-cyanopropan-2-yl)picolinesulfonamide

[1085] Step 1: Synthesis of N-(4-chloro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(2-cyanopropan-2-yl)picolinesulfonamide

[1086] 6-(5-amino-2-chlorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (100 mg, 0.29 mmol, 1.1 eq) and 4-(2-cyanopropan-2-yl)picolinic acid (50 mg, To a mixture of 0.27 mmol, and 1.0 eq) was added TEA (0.2 mL) and HATU (152 mg, 0.4 mmol, 1.5 eq). The mixture was stirred overnight at 20 °C. LCMS results indicated that the reaction performed well. H ₂ O (20 mL) was added and the reaction mixture was extracted twice with EA. The pooled extracts were washed with brine (20 mL). Concentrated in vacuo and purified by prep-HPLC (0.1% NH ₄ CO ₃ ) to obtain N-(4-chloro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(2-cyanopropan-2-yl)picolinesulfonamide (38.9 mg, 27.1% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.88 (s, 1H), 8.80 (d, J = 5.2 Hz, 1H), 8.29-8.25 (m, 3H), 8.05 (s, 1H), 7.94-7.91 (m, 1H), 7.86-7.84 (m, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.23 (s, 1H), 4.96-4.93 (m, 1H), 4.77-4.73 (m, 2H), 4.56-4.52 (m, 2H), 4.04-3.91 (m, 4H), 1.76 (s, 6H). LCMS (M+H ⁺ ) m/z: 541.15

Example 185: N-(2-chloro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(2-cyanopropan-2-yl)picolinesulfonamide (compound 185) manufacturing

[1087] Step 1: Synthesis of 6-(3-amino-2-chlorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo [1', 2': 1, 6] pyrido [2, 3-d] pyrimidin-2-amine

[1088] 디옥산/H ₂ O (25/5 mL) 중 6-브로모-N-(옥세탄-3-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (500 mg, 1.56 mmol, 1.0 eq) 및 2-클로로-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)아닐린 (512 mg, 2.02 mmol, 1.3 eq)의 혼합물에 Pd(G) ₃ (132 mg, 0.156 mmol, 0.1 eq) 및 Cs ₂ CO ₃ (1.5 g, 4.68 mmol, 3.0 eq), Ru-phos (73 mg, 0.156 mmol, 0.1 eq)를 첨가하였다. The mixture was stirred at 100 °C under N ₂ for 16 h. Concentration in vacuo and purification by silica gel column chromatography (DCM/MeOH = 10: 1) gave 6-(3-amino-2-chlorophenyl)-N-(oxetan-3-yl)-8, 9-dihydroimidazo [1', 2': 1, 6] pyrido [2, 3-d] pyrimidin-2-amine (410 mg, 71.4% yield) as a yellow solid.

[1089] Step 2: Synthesis of N-(2-chloro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(2-cyanopropan-2-yl)picolinesulfonamide

[1090] 6-(3-amino-2-chlorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (100 mg, 0.27 mmol, 1.0 eq) and 4-(2-cyanopropan-2-yl)picolinic acid in DMF (3 mL) (57 mg, 0.30 mmol, and 1.1 eq) was added DIEA (0.1 mL) and HATU (154 mg, 0.41 mmol, 1.5 eq). The mixture was stirred overnight at 20 °C. LCMS results indicated that the reaction performed well. H ₂ O (20 mL) was added and the reaction mixture was extracted twice with EA (20 mL). The pooled extracts were washed with brine (20 mL). Concentrated and purified by preparative-HPLC (0.1% NH ₄ CO ₃ ) to obtain N-(2-chloro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(2-cyanopropan-2-yl)picolinesulfonamide (14.0 mg, 9.6% aqueous rate) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ): δ 8.75 (d, J =5.2 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.42 (s, 1H), 8.30 (s, 1H), 7.82-7.80 (m, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 5.13 (t, J = 7.2Hz, 1H), 4.97-4.93 (m, 2H), 4.70-4.67 (m,, 2H), 4.26-4.21 (m, 2H), 4.04-3.99 (m, 2H), 1.81 (s, 6H). LCMS (M+H ⁺ ) m/z: 541.10.

Example 186: N-(4-chloro-2-fluoro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-cyanopropan-2-yl)benzsulfonamide (compound 186) manufacturing

[1091] Step 1: Synthesis of (3-amino-6-chloro-2-fluorophenyl)boronic acid

[1092] A solution of 4-chloro-2-fluoroaniline (2 g, 13.8 mmol) in THF (30 mL) was cooled to -65 °C and n-BuLi (15.18 mmol, 6 mL, 2.5 M in hexanes) was added. After stirring at -65 °C for 30 min, 1,2-bis(chlorodimethylsilyl)ethane (3115 mg, 14.09 mmol) in THF (8 mL) was added and after 20 min at -65 °C, an additional portion of n-BuLi (15.18 mmol, 6 mL, 2.5 M in hexanes) was added and then the cooling bath was removed. After 20 min at room temperature, the mixture was cooled to −65° C. and an additional portion of n-BuLi (15.18 mmol, 6 mL, 2.5 M in hexanes) was added and held at −65° C. for 20 min, then triisopropyl borate (7783 mg, 41.4 mmol) was added, the cooling bath was removed and stirred at room temperature under N2 for 16 h. The reaction was quenched with water, the pH was adjusted to 2.0 with 1M HCl and then extracted with EA. The organic phase was washed with saturated NaHCO ₃ , brine and concentrated. The residue was purified by flash chromatography to give (3-amino-6-chloro-2-fluorophenyl)boronic acid (570 mg, 22% yield) as a white solid. LCMS (M+H+) m/z: 189.9.

[1093] Step 2: Synthesis of 6-(3-amino-6-chloro-2-fluorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1094] (3-amino-6-chloro-2-fluorophenyl)boronic acid (200 mg, 1.06 mmol), 6-bromo-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (341 mg, 1.06 mmol) in dioxane (8 mL) and water (2 mL), A mixture of Cs2CO3 (1033 mg, 3.18 mmol) and Pd(G3) (89 mg, 0.106 mmol) and Ruphos (99 mg, 0.212 mmol) was stirred at 100° C. under N2 for 2 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH = 20/1) to give 6-(3-amino-6-chloro-2-fluorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 10% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 387.3.

[1095] Step 3: Synthesis of N-(4-chloro-2-fluoro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-cyanopropan-2-yl)benzsulfonamide

[1096] 6-(3-amino-6-chloro-2-fluorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 0.124 mmol), 3-(2-cyanopropan-2-yl)benzoic acid (23 mg, 0.1 24 mmol) and DIEA (0.5 mL) was added HATU (141 mg, 0.372 mmol). The reaction solution was stirred at 60° C. under N2 for 48 hours. The solution was diluted with EA and washed with brine. The organic phase was concentrated and purified by preparative-TLC (DCM/MeOH = 10/1, 0.1% TEA) to give the crude product which was purified by preparative-HPLC (0.1%/NH4HCO3/CH3CN/H2O) to obtain N-(4-chloro-2-fluoro-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6] Obtained pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-cyanopropan-2-yl)benzsulfonamide (1.4 mg, 2% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.33 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 6.4 Hz, 1H), 7.70 (t, J = 8.4 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.29 (s, 1H), 5.04-4.87 (m, 1H), 4.76-4.74 (m, 2H), 4.56-4.53 (m, 2H), 4.05-3.99 (m, 2H), 3.91-3.87 (m, 2H), 1.74 (s, 6H). LCMS (M+H ⁺ ) m/z: 558.0.

Example 187: 3-fluoro-N-(4-methyl-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 187) manufacturing

[1097] Step 1: Preparation of ethyl 3-fluoro-4- (trifluoromethyl) picolinate

[1098] A mixture of 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (500 mg, 2.51 mmol), AcOK (492 mg, 5.02 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (183 mg, 0.25 mmol) in EtOH (30.0 mL) was degassed and charged three times with CO The mixture was stirred at 80°C for 16 hours. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EA=10:1) to give ethyl 3-fluoro-4-(trifluoromethyl)picolinate (513 mg, 86% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 238.0.

[1099] Step 2: Synthesis of 3-fluoro-4- (trifluoromethyl) picolinic acid

[1100] A solution of ethyl 3-fluoro-4-(trifluoromethyl)picolinate (513 mg, 2.16 mmol) and LiOH H ₂ O (454 mg, 10.8 mmol) in THF (10.0 mL), CH3CN (10.0 mL) and H ₂ O (10.0 mL) was stirred at 25 °C for 2.5 hours. 2 N HCl was then added and the pH was adjusted to 5-6. The reaction mixture was extracted with EA (50 mL x2). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give 3-fluoro-4-(trifluoromethyl)picolinic acid (447 mg, 99% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 210.0.

[1101] Step 3: Synthesis of 6-(5-amino-2-methylphenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1102] 디옥산 (8.0 mL) 및 H ₂ O (0.8 mL) 중 6-브로모-N-(옥세탄-3-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (460 mg, 1.43 mmol), 4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)아닐린 (333 mg, 1.43 mmol), Cs ₂ CO ₃ (932 mg, 2.86 mmol) 및 [1,1'-비스(디페닐포스피노)페로센]디클로로팔라듐(II) (52 mg, 0.07 mmol)의 혼합물을 100℃에서 16 시간 동안 N ₂ 하에 교반하였다. The reaction mixture was concentrated and purified by column chromatography on silica gel (DCM:MeOH=20:1, +0.1%NH ₃ -MeOH), then triturated with EA (4.0 mL) to give 6-(5-amino-2-methylphenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (364 mg, 73% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 349.0.

[1103] Step 4: Synthesis of 3-fluoro-N-(4-methyl-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1104] 3-fluoro-4-(trifluoromethyl)picolinic acid (44 mg, 0.211 mmol), 6-(5-amino-2-methylphenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (70 mg, 0.201 mmol) in DMF (4.0 mL) ) and HATU (115 mg, 0.301 mmol) was added DIEA (52 mg, 0.402 mmol). The resulting mixture was stirred at room temperature for 1.5 h under N ₂ . Water was added and the reaction mixture was extracted with DCM (40 mL x3). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH=20:1, +0.1% TEA) to give 3-fluoro-N-(4-methyl-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinsulfonamide (59.1 mg, 55% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.73 (s, 1H), 8.80 (d, J = 4.8 Hz, 1H), 8.27 (s, 2H), 8.09 (t, J = 4.8 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 8.0, 2.0 Hz, 1H), 7.25-7.23 (m, 2H), 4.97 (br, 1H), 4.77 (t, J = 5.6 Hz, 2H), 4.55 (t, J = 6.0 Hz, 2H), 4.05-4.03 (m, 2H), 3.95-3.90 (m, 2H), 2.19 (s, 3H). LCMS (M+H ⁺ ) m/z: 540.4.

Example 188 and 189: N-(4-Bromo-2-fluoro-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (Compound 188) and N-(6-(2-bromo-4-fluoro-5- (4-(trifluoromethyl)picolinamido)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-N-(oxetan-3-yl)-4-(trifluoromethyl)picolinsulfonamide (compound 189) manufacturing

[1105] Step 1: Synthesis of 6-(3-amino-4-fluorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1106] 디옥산/H ₂ O (25/5 mL), Pd(dppf)Cl ₂ (102 mg, 0.13mmol, 0.05 eq) 및 Cs ₂ CO ₃ (2.4 g, 7.5 mmol, 3.0 eq) 중 6-브로모-N-(옥세탄-3-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (700 mg, 2.5mmol, 1.0 eq) 및 2-플루오로-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)아닐린 (711 mg, 3 mmol, 1.2 eq)의 혼합물을 110℃에서 N ₂ 하에 16 시간 교반하였다. Concentration and purification by column chromatography (DCM/MeOH = 10: 1) gave 6-(3-amino-4-fluorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (750 mg, 80% yield) as a yellow solid.

[1107] Step 2: Synthesis of 6-(5-amino-2-bromo-4-fluorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1108] To a solution of 6-(3-amino-4-fluorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (750 mg, 2.1 mmol, 1.0 eq) in DMF (5 mL) was added NBS (256 mg, 1.5 mmol, 0.7 eq). added. The mixture was stirred 2 h at 0 °C under N ₂ . LCMS results indicated that the reaction performed well. Concentration and purification by column chromatography gave 6-(5-amino-2-bromo-4-fluorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (410 mg, 50% yield) as a yellow solid.

[1109] Step 3: N-(4-bromo-2-fluoro-5-(2-(oxetan-3-ylamino)-8,9-dihydro imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide and N-(6-(2-bromo-4-fluoro-5-(4-(trifluoromethyl)p Synthesis of cholinamido)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-N-(oxetan-3-yl)-4-(trifluoromethyl)picolinesulfonamide

[1110] 6-(5-amino-2-bromo-4-fluorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine in DMF (3 mL) (100 mg, 0.3 mmol, 1.0 eq) and 4-(trifluoromethyl)picolinic acid (115 mg, 0.6 mmol, 2.0 eq) was added TEA (0.2 mL) and HATU (286 mg, 0.9 mmol, 2.0 eq). The mixture was stirred overnight at 20 °C. LCMS results indicated that the reaction performed well. Water was added and the reaction mixture was extracted with EA. The pooled extracts were washed with brine. 농축하고 분취형-HPLC (0.1% NH ₃ ^. H ₂ O)로 정제하여 N-(4-브로모-2-플루오로-5-(2-(옥세탄-3-일아미노)-8,9-디히드로 이미다조[1',2':1,6]피리도[2,3-d]피리미딘-6-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (4.5 mg, 3.8%) 및 N-(6-(2-브로모-4-플루오로-5-(4-(트리플루오로메틸)피콜린아미도)페닐)- 8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)-N-(옥세탄-3-일)-4-(트리플루오로메틸)피콜린설폰아미드 (5.9 mg, 5.0%)을 황색 고체로서 수득하였다. Compound 188: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (s, 1H), 9.06 (d, J = 4.8 Hz, 1H), 8.37-8.25 (m, 3H), 8.15-8.14 (m, 1H), 8.04-8.02 (m, 1H), 7.8 4-7.81 (m, 1H), 7.75 (s, 1H), 4.97-4.94 (m, 1H), 4.77-4.75 (m, 2H), 4.56-4.54 (m, 2H), 4.09-3.88 (m, 4H). LCMS (M+H ⁺ ) m/z: 604.0. 화합물 189: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (s, 1H), 9.06 (d, J = 4.8Hz, 1H), 8.68 (d, J = 5.2Hz, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.15-8.10 (m, 2H), 8.01 (d, J = 8 Hz, 1H), 7.87-7.82 (m, 2H), 7.32 (s, 1H), 5.39-5.35 (m, 1H), 4.83-4.81 (m, 4H), 3.89-3.84 (m, 2H), 3.62-3.57 (m, 2H). LCMS (M+H ⁺ ) m/z: 777.0.

Example 190: N-(5- methyl -4-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)pyridin-2-yl)-3-(trifluoromethyl)benzsulfonamide (compound 190) manufacturing

[1111] The preparation of 6-bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 133.

[1112] Step 1: Synthesis of 3- (trifluoromethyl) benzoyl chloride

[1113] A mixture of 3-(trifluoromethyl)benzoic acid (300 mg, 1.58 mmol, 1.0 eq) in SOCl ₂ (10 mL) was stirred at 80 °C for 2 h. The mixture was concentrated to give the product, 3-(trifluoromethyl)benzoyl chloride (400 mg, crude) as a yellow oil, which was used directly in the next step.

[1114] Step 2: Synthesis of N-(4-bromo-5-methylpyridin-2-yl)-3-(trifluoromethyl)-N-(3-(trifluoromethyl)benzoyl)benzsulfonamide

[1115] To a cooled (0oC) mixture of 4-bromo-5-methylpyridin-2-amine (300 mg, 1.6 mmol, 1.0 eq) and DIEA (2 mL) in DCM (20 mL) was added a solution of 3- (trifluoromethyl) benzoyl chloride (400 mg, crude) in DCM (3 mL). The mixture was stirred at room temperature for 1 hour. Water was added and the reaction mixture was extracted with DCM. The combined extracts were washed with brine and concentrated to give N-(4-bromo-5-methylpyridin-2-yl)-3-(trifluoromethyl)-N-(3-(trifluoromethyl)benzoyl)benzsulfonamide (500 mg, crude) as a yellow solid. This was used in the next step. LCMS (M+H ⁺ ) m/z: 530.8.

[1116] Step 3: Synthesis of N-(4-bromo-5-methylpyridin-2-yl)-3-(trifluoromethyl)benzsulfonamide

[1117] A mixture of N-(4-bromo-5-methylpyridin-2-yl)-3-(trifluoromethyl)-N-(3-(trifluoromethyl)benzoyl)benzsulfonamide (500 mg, crude) and K ₂ CO ₃ (500 mg) in MeOH (20 mL) was stirred at room temperature for 1 hour. The mixture was concentrated and diluted with EA (50 mL) and H ₂ O (30 mL) then the aqueous phase was extracted twice with EA (50 mL). The organic phase was washed with brine (50 mL), dried over NaSO and concentrated in vacuo to give the crude product which was purified on silica gel column flash chromatography (EtOAc : PE=1 :3 , v/v) to give the product N-(4-bromo-5-methylpyridin-2-yl)-3-(trifluoromethyl)benzsulfonamide (200 mg) as a yellow solid. LCMS (M-200) ⁺ m/z: 358.9.

[1118] Step 4: Synthesis of N-(5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3-(trifluoromethyl)benzsulfonamide

[1119] N-(4-Bromo-5-methylpyridin-2-yl)-3-(trifluoromethyl)benzsulfonamide (90 mg, 0.25 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (95 mg, 0.38 mmol) in dioxane (5 mL) , 1.5 eq), KOAc (49 mg, 0.5 mmol, 2 eq) and Pd(dppf)Cl ₂ (30 mg) was stirred at 115° C. for 16 h. The reaction was monitored by LCMS and the reaction solution was used directly in the next step. LCMS ([M-200] ⁺ m/z: 325.1.

[1120] Step 5: Synthesis of N-(5-methyl-4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-3-(trifluoromethyl)benzsulfonamide

[1121] N- (5-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) -3- (trifluoromethyl) benzsulfonamide (reaction solution), 6-bromo-N-methyl-8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (80 mg, 0.28 mmol, 1.0 eq), K2CO3 (118 mg, 0.86 mmol, 3.0 eq) and Pd(dppf)Cl2 (30 mg) was stirred at 110° C. for 16 h. Water was added and the reaction mixture was extracted with DCM. The organic phase was washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product which was purified by silica gel column flash chromatography (DCM : MeOH=20:1 , v/v) and preparative-HPLC (0.1% NH ₄ HCO ₃ ) to N-(5-methyl-4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6] Obtained pyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-3-(trifluoromethyl)benzsulfonamide (15 mg, 11% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 8.39 (s, 1H), 8.31-8.24 (m, 3H), 8.11 (s, 1H), 7.98-7.96 (m, 1H), 7.79-7.75 (m, 1H), 7.61-7 .54 (m, 1H), 7.29 (s, 1H), 4.17-3.86 (m, 4H), 2.86 (s, 3H), 2.18 (s, 3H). LCMS (M+H ⁺ ) m/z: 480.0.

Example 191 N-(6- methyl -5-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)pyridin-3-yl)-4-(trifluoromethyl)picolinesulfonamide (compound 191) manufacturing

[1122] Step 1: Synthesis of N-(5-bromo-6-methylpyridin-3-yl)-4-(trifluoromethyl)picolinesulfonamide

[1123] A mixture of 4-(trifluoromethyl)picolinic acid (191 mg, 1.0 mmol) in SOCl ₂ (3 mL) was stirred at 80 °C for 1 hour. The reaction was concentrated to give a solid. The solid product was dissolved in DCM (2 mL) and then it was added to a mixture of TEA (300 mg, 3.0 mmol), 5-bromo-6-methylpyridin-3-amine (187 mg, 1.0 mmol) in DCM (5 mL) at room temperature. The reaction was stirred at 25 °C for 3 hours. The reaction mixture was poured into water and extracted with DCM (30 mLx2). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , concentrated and flash purified to give N-(5-bromo-6-methylpyridin-3-yl)-4-(trifluoromethyl)picolinesulfonamide (170 mg, 47% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 360.0.

[1124] Step 2: Synthesis of (2-methyl-5-(4-(trifluoromethyl)picolinamido)pyridin-3-yl)boronic acid

[1125] N-(5-bromo-6-methylpyridin-3-yl)-4-(trifluoromethyl)picolinesulfonamide (72 mg, 0.2 mmol, 1.0 equiv), Pin ₂ B ₂ (76 mg, 0.3 mmol, 1.5 equiv), KOAc (60 mg, 0.6 mmol, 3.0 equiv), and PdCl ₂ in 1,4-dioxane (2 mL) (dppf) (29 mg, 0.04 mmol, 20 mol %) was refluxed under N ₂ for 3 h. The reaction solution was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 325.0.

[1126] Step 3: Synthesis of N-(6-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)pyridin-3-yl)-4-(trifluoromethyl)picolinesulfonamide

[1127] (2-methyl-5-(4-(trifluoromethyl)picolinamido)pyridin-3-yl)boronic acid (above solution, 0.2 mmol, 1.0 equiv) in 1,4-dioxane (3 mL) and H ₂ O (0.5 mL), 6-bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] Pyrimidine-2-amine (54 mg, 0.2 mmol, 1.0 equiv), K ₂ CO ₃ (82 mg, 0.6 mmol, 3.0 equiv), and PdCl ₂ (dppf) (28 mg, 0.04 mmol, 20 mol %) was stirred at 90° C. for 2 h under N2. The reaction mixture was concentrated and purified by prep-HPLC to give N-(6-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)pyridin-3-yl)-4-(trifluoromethyl)picolinesulfonamide (16.7 mg, 17% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.05 (d, J = 5.2 Hz, 1H), 8.91 (d, J = 2.8 Hz, 1H), 8.35 (s, 1H), 8.26-8.20 (m, 2H), 8.12 (d, J = 4.8 Hz, 1H), 7.48 (s, 1H), 7.23 (s, 1H), 6.09 (s, 1H), 4.08–3.90 (m, 4H), 2.67 (s, 3H), 2.40 (s, 3H). LCMS (M+H ⁺ ) m/z: 481.0.

Example 192 N-(5- methyl -6-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)pyridin-2-yl)-4-(trifluoromethyl)picolinesulfonamide (compound 192) manufacturing

[1128] Step 1: Synthesis of N-(6-bromo-5-methylpyridin-2-yl)-4-(trifluoromethyl)picolinesulfonamide

[1129] To a solution of 4-(trifluoromethyl)picolinic acid (700 mg, 1.90 mmol) in DMF (10 mL) was added 6-bromo-5-methylpyridin-2-amine (753 mg, 4.03 mmol), HATU (2.0 g, 5.49 mmol) and TEA (1.4 g, 10.9 mmol). The mixture was stirred at room temperature under N ₂ for 16 hours. The mixture was diluted with water (50 mL) then extracted with EA (30 mL x 3). The residue was purified by silica gel column chromatography (PE : EA = 10 : 1) to give N-(6-bromo-5-methylpyridin-2-yl)-4-(trifluoromethyl)picolinesulfonamide (750 mg, 57% yield) as a white solid. LCMS (M+H+) m/z: 361.9.

[1130] Step 2: Synthesis of N-(5-methyl-6-(trimethylstannyl)pyridin-2-yl)-4-(trifluoromethyl)picolinesulfonamide

[1131] To a solution of N-(6-bromo-5-methylpyridin-2-yl)-4-(trifluoromethyl)picolinesulfonamide (150 mg, 0.42 mmol) in toluene (5 mL) 1,1,1,2,2,2-hexamethyl distanane (273 mg, 0.83 mmol), Pd(PPh ₃ ) ₄ (48 mg, 0.042 mmol) was added. The mixture was stirred at 90° C. under N ₂ for 16 h. The mixture was concentrated, diluted with DCM (5 mL), filtered and the filtrate was concentrated to give N-(5-methyl-6-(trimethylstannyl)pyridin-2-yl)-4-(trifluoromethyl)picolinesulfonamide (430 mg, crude) as a gray solid. LCMS (M+H ⁺ ) m/z: 446.0.

[1132] Step 3: Synthesis of N-(5-methyl-6-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-4-(trifluoromethyl)picolinesulfonamide

[1133] N-(5-methyl-6-(trimethylstannyl)pyridin-2-yl)-4-(trifluoromethyl)picolinesulfonamide (330 mg in 1,4-dioxane (3 mL) , 0.32 mmol) in a solution of 6-bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (107 mg, 0.38 mmol), Pd(dppf)Cl ₂ (23 mg, 0.032 mmol), CuI (5 mg, 0.032 mmol) and CsF (6 mg, 0.75 mmol) were added. The mixture was stirred at 130° C. under MW for 8 hours. The mixture was filtered and purified by prep-HPLC (0.1%/HCl/CH ₃ CN/H ₂ O) to obtain N-(5-methyl-6-(2-(methylamino)-8,9-dihydroimidazo [1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-4-(trifluoromethyl)picolinesulfonamide (50.4 mg, 33% yield) was obtained as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.95 (s, 1H), 10.19 (s, 1H), 9.09 (d, J = 5.2 Hz, 1H), 8.94 (s, 1H), 8.63 (t , J = 4.4 Hz, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 8.18 (d, J = 4.4 Hz, 1H), 8.12 (d, J = 4.8 Hz, 1H), 7.99 (d , J = 8.4 Hz, 1H), 4.68–4.55 (m, 2H), 4.17 (t, J = 10.0 Hz, 2H), 2.98 (d, J = 4.8 Hz, 3H), 2.45 (s, 3H). LCMS (M+H ⁺ ) m/z: 481.4.

Example 193: 3-(4-fluorophenyl)-1-isopropyl-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxsulfonamide (compound 193) manufacturing

[1134] Step 1: Synthesis of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl chloride

[1135] To a mixture of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (50 mg, 0.2 mmol, 1.0 eq) in DMF (1 drop) and DCM (2 mL) was added oxalyl chloride (2 mL) and the mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo to give 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl chloride (80 mg, crude) as a yellow oil which was used directly in the next step. LCMS (M+H ⁺ ) m/z: 307.1

[1136] Step 2: Synthesis of 3-(4-fluorophenyl)-1-isopropyl-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxsulfonamide

[1137] A mixture of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (50 mg, 0.2 mmol, 1.0 eq) and DIEA (0.5 mL) in DCM (2 mL) was stirred at room temperature. Then 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl chloride (80 mg crude) in DCM (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column flash chromatography (EtOAc: PE=1:3, v/v) to obtain 3-(4-fluorophenyl)-1-isopropyl-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-Carboxsulfonamide (45 mg, 44% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 507.9

[1138] Step 3: Synthesis of 3-(4-fluorophenyl)-1-isopropyl-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxsulfonamide

[1139] 디옥산 (6 mL) 중 3-(4-플루오로페닐)-1-이소프로필-N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-2,4-디옥소-1,2,3,4-테트라히드로피리미딘-5-카르복스설폰아미드 (45 mg, 0.09 mmol, 1.0eq), K ₂ CO ₃ (37 mg, 0.27 mmol, 3.0eq), Pd(dppf)Cl ₂ (10 mg, 0.014 mmol) 및 6-브로모-N-메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (25 mg, 0.09 mmol, 1.0eq)의 혼합물을 100℃에서 3시간 교반하였다. The mixture was purified by preparative-HPLC (0.1% FA) to obtain 3-(4-fluorophenyl)-1-isopropyl-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate. Sulfonamide (8.3 mg, 16% yield) was obtained as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.85 (s, 1H), 8.62 (s, 1H), 8.35 (s, 1H), 7.60-7.53 (m, 3H), 7.47-7.30 (m, 5H), 7.23-7.22 (m, 1H), 4.80 −4.73 (m, 1H), 4.21–4.04 (m, 2H), 3.94–3.89 (m, 2H), 2.87 (s, 3H), 2.18 (s, 3H), 1.41 (d, J = 6.8 Hz, 6H). LCMS (M+H ⁺ ) m/z: 581.0.

Example 194: N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxsulfonamide (compound 194) manufacturing

[1140] The preparation of 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 139.

[1141] Step 1: N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxsulfone synthesis of amides

[1142] HATU (86 mg, 0.23 mmol) was added to 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.15 mmol), 3-(4-fluorophenyl)-1-isopropyl-2,4 in DMF (2 mL) -dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (50 mg, 0.17 mmol), DIEA (58 mg, 0.45 mmol) was added to the mixture. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mLx2). The combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product which was purified by preparative-HPLC (0.1% HCOOH) to N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3 Obtained -(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxsulfonamide formate (23.5 mg, 18% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.06 (s, 1H), 8.62 (s, 1H), 8.25 (d, J = 8.0 Hz, 2H), 8.16 (s, 1H), 7.52-7.41 (m, 3H), 7.37-7.33 (m, 2H), 7.20 (d, J = 12.0 Hz, 2H), 4.78-4.74 (m, 1H), 4.08-3.99 (m, 2H), 3.93-3.89 (m, 2H), 2.85 (s, 3H), 2.18 (s, 3H), 1.40 (d, J = 6.8 Hz, 6H). LCMS (M+H ⁺ ) m/z: 599.7.

Example 195: N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 195) manufacturing

[1143] The preparation of 6-bromo-N-(6-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 102.

[1144] Step 1: Synthesis of N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1145] 디옥산/H ₂ O (120 mL/20 mL) 중 6-브로모-N-(1-메틸-1H-피라졸-4-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (3.5 g, 10.12 mmol)의 용액에 N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (4.1 g, 10.12 mmol), Pd(dppf)Cl ₂ (740 mg, 1.01 mmol), Cs ₂ CO ₃ (9.9 g, 30.35 mmol)를 첨가하고, 혼합물을 16 시간 동안 100℃에서 N ₂ 하에 교반하였다. The reaction mixture was concentrated and purified by column chromatography (DCM:MeOH=20:1) to obtain N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinsulfonamide (1.6 g, 29.1% yield) was obtained as a yellow solid.

[1146] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.93 (s, 1H), 10.83 (s, 1H), 9.92 (s, 1H), 9.06 (d, J = 4.8 Hz, 1H), 9.01 (s, 1H), 8.34 (s, 1H), 8.22 (d, J = 6.4 Hz, 1H), 8.12 (d, J = 4.4 Hz, 1H), 8.06 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 8.4, 2.0 Hz, 1H), 7.72 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 4.81 (t, J = 10.0 Hz, 2H), 4.10–4.06 (m, 2H), 3.90 (s, 3H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 546.3.

Example 196: 4-(2-fluoropropan-2-yl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide (compound 196) manufacturing

[1147] Step 1: Synthesis of 6-(5-amino-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1148] 디옥산 (6 mL) 및 물 (2 mL) 중 6-브로모-N-(1-메틸-1H-피라졸-4-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (300 mg, 0.87 mmol), 4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)아닐린 (202 mg, 0.87 mmol), Cs ₂ CO ₃ (848 mg, 2.60 mmol) 및 Pd(dppf)Cl ₂ (64 mg, 0.087 mmol)의 혼합물을 탈기하고, N ₂ 로 3회 충전한 다음 100℃에서 2시간 교반하였다. The reaction mixture was concentrated. The residue is purified by column chromatography (DCM/MEOH = 20/1, +0.5% Tea) and 6- (5-amino-2-methylphenyl) -N- (1-methyl-1H-pyrazol-4-yl) -8,9-Dihydro Dazo [1 ', 2': 1 ':' 2,3-D] Pyrimidine-2-amine (200 mg) 62.1% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 373.2.

[1149] Step 2: Synthesis of 2-(2-chloropyridin-4-yl)propan-2-ol

[1150] To a mixture of 2-chloro-4-iodopyridine (500 mg, 2.09 mmol) in dry THF (10 mL) was added n-BuLi (1.3 mL, 1.6 M, 2.09 mmol) at -78 °C and stirred for 15 minutes, then propan-2-one (364 mg, 6.27 mmol) was added. The mixture was stirred at -78 °C for 2 hours. The reaction mixture was quenched with NH ₄ Cl aq (20 mL) and extracted with EA (20 mL x 3), dried over Na ₂ SO ₄ and filtered. The combined organic layers were concentrated in vacuo and purified by column chromatography on silica gel (PE/EA=5/1) to give 2-(2-chloropyridin-4-yl)propan-2-ol (250 mg, 69.7% yield) as a white solid. LCMS (MH) ^- m/z: 170.2.

[1151] Step 3: Synthesis of 2-chloro-4- (2-fluoropropan-2-yl) pyridine

[1152] A mixture of 2-(2-chloropyridin-4-yl)propan-2-ol (240 mg, 1.4 mmol) in dry DCM (10 mL) was cooled to 0 °C and then DAST (560 mg, 3.5 mmol) was added dropwise. The mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with NaHCO ₃ aq (20 mL) and extracted with EA (20 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and filtered. Concentration and purification by column chromatography on silica gel (PE/EA=5/1) gave 2-chloro-4-(2-fluoropropan-2-yl)pyridine (130 mg, 53.7% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 174.1.

[1153] Step 4: Synthesis of ethyl 4-(2-fluoropropan-2-yl)picolinate

[1154] 2-chloro-4-(2-fluoropropan-2-yl)pyridine (130 mg, 0.75 mmol) in EtOH (20 mL), AcOK (293 mg, 3.0 mmol) and Pd(dppf)Cl ₂ (27 mg, 0.04 mmol) was degassed, charged with CO three times and stirred at 80° C. for 16 h under CO. The reaction mixture was concentrated and purified by column chromatography on silica gel (PE: EA=4:1) to give ethyl 4-(2-fluoropropan-2-yl)picolinate (120 mg, 82% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 212.1.

[1155] Step 5: Synthesis of 4-(2-fluoropropan-2-yl)picolinic acid

[1156] To a mixture of ethyl 4-(2-fluoropropan-2-yl)picolinate (120 mg, 0.57 mmol) in MeOH (5 mL) and H ₂ O (5 mL) was added LiOH (70 mg, 2.84 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with NH ₄ Cl aq. and the aqueous phase was adjusted to pH=2-3 with 1N HCl, then extracted with EA (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified by prep-HPLC (0.1% FA) to give 4-(2-fluoropropan-2-yl)picolinic acid (80 mg, 77% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 184.0.

[1157] Step 6: Synthesis of 4-(2-fluoropropan-2-yl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide

[1158] 6-(5-amino-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 0.11 mmol), 4-(2-fluoropropan-2-yl)picolinic acid (22 mg, 0.12 mmol), HATU (82 mg, 0.22 mmol) and DIEA (42 mg, 0.32 mmol) were stirred at room temperature for 2 hours. The reaction mixture was diluted with H ₂ O (20 mL), extracted with DCM (20 mLx3), dried over Na ₂ SO ₄ and filtered. The combined organic layers were concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=10/1) to give the crude product which was purified by preparative-HPLC (0.1% NH ₃ -H ₂ O) to give 4-(2-fluoropropan-2-yl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo [ Obtained 1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide (17 mg, 26.4 % yield) as a yellow solid.

[1159] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.64 (s, 1H), 10.07 (br, 1H), 8.74 (d, J = 5.2 Hz, 1H), 8.49 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 5.2, 1.6 Hz, 1H), 7.60-7.47 (m, 2H), 7.27 (d, J = 7.6 Hz, 1H), 4.38-4.33 (m, 2H), 4.00-3.94 (m, 2H), 3.88 (s, 3H), 2.21 (s, 3H), 1.73 (s, 3H), 1.69 (s, 3H). LCMS (M+H ⁺ ) m/z: 538.4.

Example 197: 4-(1,1-difluoroethyl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide (compound 197) manufacturing

[1160] Step 1: Synthesis of 2-bromo-4- (1,1-difluoroethyl) pyridine

[1161] To a solution of 1-(2-bromopyridin-4-yl)ethan-1-one (950 mg, 4.75 mmol) in DCM (10 mL) was added DAST (1.9 g, 11.88 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight, quenched with NaHCO ₃ (aq.) (20 mL) and extracted with DCM (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EA=5:1) to give 2-bromo-4-(1,1-difluoroethyl)pyridine (630 mg, 60.3% yield) as a yellow oil.

[1162] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.56 (d, J=5.2 Hz, 1 H), 7.85 (s, 1 H), 7.65 (d, J=4.8 Hz, 1 H), 2.00 (t, J=19.4 Hz, 3 H).

[1163] Step 2: Synthesis of ethyl 4- (1,1-difluoroethyl) picolinate

[1164] To a solution of 2-bromo-4-(1,1-difluoroethyl)pyridine (630 mg, 2.84 mmol) in EtOH (10 mL) was added AcOK (834 mg, 8.51 mmol) and Pd(dppf)Cl ₂ (208 mg, 0.28 mmol). The resulting mixture was stirred at 80° C. for 3 h under CO. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EA=3:1) to give ethyl 4-(1,1-difluoroethyl)picolinate (600 mg, 98.4% yield) as a yellow oil. LCMS (M+H ⁺ ) m/z: 216.2

[1165] Step 3: Synthesis of 4-(1,1-difluoroethyl)picolinic acid

[1166] To a solution of ethyl 4-(1,1-difluoroethyl)picolinate (600 mg, 2.78 mmol) in MeOH/H ₂ O (10 mL/2 mL) was added LiOH (201 mg, 8.37 mmol). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated to remove MeOH and the aqueous phase was adjusted to pH=2-3 with 1N HCl then extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 4-(1,1-difluoroethyl)picolinic acid (440 mg, 84.4% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 188.2.

[1167] Step 4: Synthesis of 4-(1,1-difluoroethyl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide

[1168] 6-(5-amino-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (100 mg, 0.27 mmol), 4-(1,1-difluoroethyl)picolinic acid (50 mg, 0. 27 mmol), HATU (153 mg, 0.40 mmol) and DIEA (104 mg, 0.81 mmol) were stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL), the resulting solids were filtered and the filter cake was purified by preparative-HPLC (0.1% NH ₃ H ₂ O) to yield 4-(1,1-difluoroethyl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyridonium Obtained midin-6-yl)phenyl)picolinesulfonamide (30.8 mg, 21.2% yield) as a yellow solid.

[1169] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.68 (s, 1H), 9.80 (br, 1H), 8.89 (d, J = 4.8 Hz, 1H), 8.32 (s, 1H), 8.22 (d, J = 0.8 Hz, 1H), 7.93 (s, 1H) ), 7.86 (dd, J = 4.8, 2.0 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.56 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H), 4.25–4.19 (m, 2H), 3.97 (t, J = 8.8 Hz, 2H), 3.83 (s, 3H), 2.22 ( s, 3H), 2.05 (t, J = 19.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 542.4.

Example 198: 4-(tert-butyl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide (compound 198) manufacturing

[1170] Step 1: Synthesis of 4-(tert-butyl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide

[1171] 6-(5-amino-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (100 mg, 0.27 mmol), 4-(tert-butyl)picolinic acid (58 mg, 0.27 mmol) in DMF (3 mL) , HATU (153 mg, 0.40 mmol) and DIEA (104 mg, 0.81 mmol) were stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL), the resulting solid was filtered and the filter cake was purified by prep-HPLC (0.1% NH ₃ H ₂ O) to yield 4-(tert-butyl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6 Obtained -yl)phenyl)picolinesulfonamide (30.2 mg, 21.1% yield) as a yellow solid.

[1172] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.56 (s, 1H), 9.78 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.30 (s, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.93 (s, 1H) ), 7.83 (d, J = 2.0 Hz, 1H), 7.76 (dd, J = 8.4, 2.0 Hz, 1H), 7.69 (dd, J =5.2, 2.0 Hz, 1H), 7.56 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 4.21-4.17 (m, 2H), 3.97 (t, J = 8.8 Hz, 2H), 3.83 (s, 3H), 2.22 (s , 3H), 1.34 (s, 9H). LCMS (M+H ⁺ ) m/z: 534.4.

Example 199: 4-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9- Dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide (compound 199) manufacturing

[1173] Step 1: Synthesis of 4-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide

[1174] 6-(5-amino-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (150 mg, 0.40 mmol), 4-(2-cyanopropan-2-yl)picolinic acid (77 mg, 0.40 mmol), HATU (230 mg, 0.60 mmol) and DIEA (156 mg, 1.21 mmol) were stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% NH ₃ H ₂ O) to give 4-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide (66 .8 mg, 30.5% yield) as a yellow solid.

[1175] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.64 (s, 1H), 9.78 (br, 1H), 9.79 (d, J = 5.2 Hz, 1H), 8.30 (s, 1H), 8.26-8.25 (m, 1H), 7.93 (s, 1H), 7.84-7.82 (m, 2H), 7.77 (dd, J = 8.4, 2.4 Hz, 1H), 7.56 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 4.21–4.17 (m, 2H), 3.99–3.95 (m, 2H), 3.82 (s, 3H), 2.22 (s, 3H), 1.76 (s, 6H). LCMS (M+H ⁺ ) m/z: 545.3.

Example 200: 4-(2-hydroxypropan-2-yl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide (compound 200) manufacturing

[1176] Step 1: Synthesis of 4-(2-hydroxypropan-2-yl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide

[1177] 6-(5-amino-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (85 mg, 0.23 mmol) in DMF (3 mL), 4-(2-hydroxypropan-2-yl)picolinic acid (248 mg tablet), 1.37 mmol), HATU (130 mg, 0.34 mmol) and DIEA (88 mg, 0.69 mmol) were stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% NH ₃ H ₂ O) to obtain 4-(2-hydroxypropan-2-yl)-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide (25 .5 mg, 20.9% yield) as a yellow solid.

[1178] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.56 (s, 1H), 9.77 (s, 1H), 8.65 (d, J = 5.2 Hz, 1H), 8.32 (s, 1H), 8.25 (d, J = 1.2 Hz, 1H), 7.93 (s, 1H) ), 7.83 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 8.4, 2.4 Hz, 1H), 7.72 (dd, J = 5.2, 1.6 Hz, 1H), 7.56 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 5.45 (s, 1H), 4.20-4.17 (m, 2H), 4.00-3.96 (m, 2H), 3.83 (s, 3H), 2.22 (s, 3H), 1.47 (s, 6H). LCMS (M+H ⁺ ) m/z: 536.5.

Example 201: N-(2-fluoro-4-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(2-hydroxypropan-2-yl)picolinesulfonamide (compound 201) manufacturing

[1179] Step 1: N-(2-fluoro-4-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(2-hydroxypropan-2-yl)picolinesulfonamide

[1180] 6-(5-amino-4-fluoro-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (90 mg, 0.23 mmol) in DMF (3 mL), 4-(2-hydroxypropan-2-yl)picolinic acid (2 A mixture of 50 mg (crude), 1.38 mmol), HATU (131 mg, 0.35 mmol) and DIEA (90 mg, 0.69 mmol) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% NH ₃ H ₂ O) to N-(2-fluoro-4-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(2-hydroxypropan-2-yl)picolinesulfone. The amide (16.9 mg, 13.2% yield) was obtained as a yellow solid.

[1181] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.37 (s, 1H), 9.79 (s, 1H), 8.67 (d, J = 4.4 Hz, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.75 (d, J = 4.4 Hz, 1H), 7.56 (s, 1H), 7.25 (d, J = 12.0 Hz, 1H), 7.20 (s, 1H), 5.48 (s, 1H), 4.18-4.10 (m, 2H), 3.99-3.97 (m, 2H), 3.83 (s, 3H), 2.25 (s, 3H), 1.47 (s, 6H). LCMS (M+H ⁺ ) m/z: 554.2.

Example 202: 4-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide (compound 202) manufacturing

[1182] Step 4: Synthesis of 4-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide

[1183] 6-(5-amino-4-fluoro-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (150 mg, 0.38 mmol) in DMF (5 mL), 4-(2-cyanopropan-2-yl)picolinic acid ( A mixture of 73 mg, 0.38 mmol), HATU (220 mg, 0.58 mmol) and DIEA (149 mg, 1.15 mmol) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% NH ₃ H ₂ O) to obtain 4-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinic acid. Ponamide (66.8 mg, 30.5% yield) was obtained as a yellow solid.

[1184] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.40 (s, 1H), 9.81 (br, 1H), 8.82 (d, J = 5.2 Hz, 1H), 8.30 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 7.92-7.86 (m, 3H), 7.56-7.54 (m, 1H), 7.27 (d, J = 11.6 Hz, 1H), 7.20 (s, 1H), 4.20-4.17 (m, 2H), 3.99-3.95 (m, 2H), 3.82 (s, 3H), 2.25 (s, 3H), 1.76 (s, 6H). LCMS (M+H ⁺ ) m/z: 563.3.

Example 203: N-(2-fluoro-4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide (compound 203) manufacturing

[01185 Step 1: Synthesis of N-(2-fluoro-4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide

[1186] 6-(3-amino-2-fluoro-6-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (30 mg, 0.077 mmol, 1.0 eq) and picolinic acid (14 mg, 0.1 To a solution of 2mmol, 1.2 eq) was added DIEA (0.1 mL) and HATU (58 mg, 0.15 mmol, 2.0 eq). The mixture was stirred at 20° C. under N2 for 1 hour. LCMS results indicated that the reaction performed well. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1% FA) to afford N-(2-fluoro-4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide (6.0 mg, 17% yield) as a yellow solid. did

[1187] ¹ H NMR (400 MHz, CD ₃ OD): δ 8.72-8.70 (m, 1H), 8.62-8.59 (m, 1H), 8.30-8.26 (m, 2H), 8.08-8.03 (m, 2H), 7.73-7.63 (m, 3H), 7.26 -7.24 (m, 1H), 4.63-4.59 (m, 2H), 4.16-4.12 (m, 2H), 3.94 (s, 3H), 2.31 (s, 3H). LCMS (M+H ⁺ ) m/z: 496.0.

Example 204: 2 - Fluoro -N-(4- methyl -3-(2-((1- methyl -1H- pyrazole -4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzsulfonamide (compound 204) manufacturing

[1188] Step 1: Synthesis of 2-fluoro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzsulfonamide formic acid salt

[1189] 6-(5-amino-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.16 mmol), 2-fluorobenzoic acid (27 mg, 0.19 mmol) and HATU (92 mg, 0.24 mmol), DIEA (0.1 mL) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction was purified by preparative-HPLC (0.1% FA) to give 2-fluoro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzsulfonamide formic acid salt (16.5 mg, 21% yield). Obtained as a yellow solid.

[1190] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.37 (s, 1H), 9.82-9.67 (m, 1H), 8.32 (s, 1H), 8.23 (s, 2H), 7.92 (s, 1H), 7.64-7.60 (m, 2H), 7.58-7.67 (m, 3H), 7.34-7.33 (m, 2H), 7.22-7.19 (m, 2H), 4.24-4.15 (m, 2H), 3.99-3.97 (m, 2H), 3.82 (s, 3H), 2.20 (s, 3H). LCMS (M+H+) m/z: 495.2.

Example 205: 3-fluoro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide (compound 205) manufacturing

[1191] Step 1: Synthesis of 3-fluoro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide

[1192] 6-(5-amino-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.16 mmol), 3-fluoropicolinic acid (23 mg, 0.16 mmol), HATU ( A mixture of 122 mg, 0.32 mmol) and DIEA (62 mg, 0.48 mmol) was stirred at room temperature for 2 hours. The reaction mixture was diluted with H ₂ O (20 mL), extracted with DCM (30 mL x 3), dried over Na ₂ SO ₄ and filtered. The combined organic layers were concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=15/1) to give the crude product which was purified by pre-HPLC (0.1% HCOOH) and pre-HPLC (0.1% NH ₃ -H ₂ O) to obtain 3-fluoro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydride Obtained roimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)picolinesulfonamide (28.1 mg, 35% yield) as a yellow solid.

[1193] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.56 (s, 1H), 9.78 (s, 1H), 8.55 (d, J = 4.4 Hz, 1H), 8.31 (s, 1H), 7.99-7.80 (m, 2H), 7.76-7.68 (m, 2H), 7.65 (dd, J = 8.4, 2.4 Hz, 1H), 7.55 (s, 1H), 7.25-7.15 (m, 2H), 4.19 (s, 2H), 3.98 (t, J = 8.4 Hz, 2H), 3.78 (s, 3H), 2.21 (s, 3H). LCMS (M+H ⁺ ) m/z: 496.3.

Example 206: 2 - Fluoro -N-(4- methyl -3-(2-((4- morpholinophenyl )amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzsulfonamide (compound 206) manufacturing

[1194] Step 1: Synthesis of 6-bromo-N-(4-morpholinophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1195] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (550 mg, 1.76 mmol) in DMSO (10 mL) was added 4-morpholinoaniline (469 mg, 2.64 mmol) and the mixture was stirred at 120°C for 2 hours. The reaction mixture was poured into water, filtered and the filter-cake was washed with water and dried in vacuo to give 6-bromo-N-(4-morpholinophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (690 mg, 92.0% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 426.9 and 428.9

[1196] Step 2: Synthesis of 6-(5-amino-2-methylphenyl)-N-(4-morpholinophenyl)-8,9-dihydroimidazo[1',2':1,6]pyr ido[2,3-d]pyrimidin-2-amine

[1197] To a solution of 6-bromo-N-(4-morpholinophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (190 mg, 0.44 mmol) in dioxane/H ₂ O (8 mL/2 mL) was added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxy Saborolan-2-yl)aniline (104 mg, 0.44 mmol), Pd(dppf)Cl ₂ (33 mg, 0.044 mmol), Cs ₂ CO ₃ (435 mg, 1.33 mmol) were added. The mixture was stirred under N ₂ at 100° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH=20:1) to give 6-(5-amino-2-methylphenyl)-N-(4-morpholinophenyl)-8,9-dihydroimidazo[1',2':1,6]pyr ido[2,3-d]pyrimidin-2-amine (200 mg, 99% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 454.3.

[1198] Step 3: Synthesis of 2-fluoro-N-(4-methyl-3-(2-((4-morpholinophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzsulfonamide

[1199] 2-fluorobenzoic acid (31 mg, 0.22 mmol), HATU (126 mg, 0.33 mmol), DIPEA (85 mg, 0.66 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture and the resulting solid was filtered. The filtered cake was purified by prep-HPLC (0.1% NH ₃ `H ₂ O) to give 2-fluoro-N-(4-methyl-3-(2-((4-morpholinophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzsulfonamide (24.4 mg, 19.2% yield) was obtained as a yellow solid.

[1200] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.37 (s, 1H), 9.60 (s, 1H), 8.31 (s, 1H), 7.69-7.64 (m, 4H), 7.58-7.56 (m, 2H), 7.37-7.31 (m, 2H), 7.21 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 6.91 (d, J = 8.8 Hz, 2H), 4.10 (t, J = 9.2 Hz, 2H), 3.95 (t, J = 9.2 Hz, 2H), 3.74 (s, 4H), 3.04 (s, 4H), 2.20 (s, 3H). LCMS (M+H ⁺ ) m/z: 576.1.

Example 207: N-(4-methyl-3-(2-((6-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzsulfonamide (compound 207) manufacturing

[1201] Step 1: Synthesis of N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(trifluoromethyl)benzsulfonamide

[1202] 3-(trifluoromethyl)benzoic acid (2.34 g, 12.3 mmol) in DMF (35.0 mL), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2- A mixture of dioxaborolan-2-yl)aniline (3.0 g, 12.9 mmol), DIEA (4.6 g, 36.0 mmol) and HATU (7.0 g, 18.0 mmol) was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water (150 mL) and extracted with EA (100 mL x 2). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA=10/1) to obtain N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 Obtained -yl)phenyl)-3-(trifluoromethyl)benzsulfonamide (4.5 g, 90% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 406.2.

[1203] Step 2: Synthesis of 6-bromo-N-(6-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1204] A mixture of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (3.8 g, 12 mmol) and 6-methylpyridin-3-amine (1.96 g, 18.0 mmol) in DMSO (50.0 mL) was degassed, charged three times with N ₂ and then charged with 12 Stirred at 0°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (500 mL), stirred at room temperature for 3.0 hours and then filtered. The collected cake was dried to give 6-bromo-N-(6-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (2.76 g, 63.7% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 356.9 and 358.9

[1205] Step 3: Synthesis of N-(4-methyl-3-(2-((6-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzsulfonamide

[1206] 디옥산 (30.0 mL) 및 물 (3.0 mL) 중 6-브로모-N-(6-메틸피리딘-3-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d] 피리미딘-2-아민 (1.6 g, 4.48 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-3-(트리플루오로메틸)벤즈설폰아미드 (1.9 g, 4.7 mmol), Cs ₂ CO ₃ (4.38 g, 13.44 mmol) 및 Pd(dppf)Cl ₂ (328 mg, 0.45 mmol)의 혼합물을 탈기하고, N ₂ 로 3회 충전한 다음 100℃에서 16 시간 교반하였다. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by column chromatography (DCM/MeOH=30/1, +0.5% TEA) to give the crude product which was triturated with EA (40 mL) and filtered to obtain N-(4-methyl-3-(2-((6-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-( Trifluoromethyl)benzsulfonamide (1.155 g, 46% yield) was obtained as a yellow solid.

^{[1207] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 10.45 (s, 1H), 9.89 (s, 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.12 (dd, J = 8.8, 2.4 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.69-7.67 (m, 2H), 7.26-7.23 (m, 2H), 7.18 (d, J = 8.4 Hz, 1H), 4.13 (t, J = 9.6 Hz, 2H), 3.97 (t, J = 9.2 Hz, 2H), 2.41 (s, 3H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 556.5.

Example 208: N-(4-methyl-3-(2-((6-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 208) manufacturing

[1208] Step 1: Synthesis of N-(4-methyl-3-(2-((6-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1209] 6-Bromo-N-(6-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2': in dioxane/H ₂ O (20 mL/5 mL): N-(4-methyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (635 mg, 1.56 mmol), Pd(dppf)Cl ₂ (114 mg, 0.156 mmol) ), Cs ₂ CO ₃ (1.5 g, 4.68 mmol) were added and the mixture was stirred at 120° C. for 2 h under N ₂ . The reaction mixture was concentrated and purified by column chromatography (EA:MeOH=10:1) to obtain N-(4-methyl-3-(2-((6-methylpyridin-3-yl)amino)-8,9- Dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (380 mg, 44% yield) was obtained as a yellow solid.

[1210] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.77 (s, 1H), 9.90 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.39 (s, 1H), 8.34 (s, 1H), 8.14-8.08 (m, 2H), 7.82 (d, J=1.6 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.26-7.24 (m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 4.14-4.12 (m, 2H), 4.00-3.97 (m, 2H), 2.42 (s, 3H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 557.2.

Example 209: N-(4-methyl-3-(2-((2-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 209) manufacturing

[1211] Step 1: Synthesis of 6-bromo-N-(2-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1212] A mixture of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (106 mg, crude) and 2-methylpyridin-3-amine (73 mg, 0.56 mmol) in DMSO (5 mL) was stirred at 120°C for 16 hours. The reaction mixture was purified by preparative-HPLC (0.1% NH ₃ ^. H ₂ O) to afford 6-bromo-N-(2-methylpyridin-3-yl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 33% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 357.1 and 359.1.

[1213] Step 2: Synthesis of N-(4-methyl-3-(2-((2-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide formic acid

[1214] (6-Bromo-N-(2-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 0.11 mmol) in dioxane (10 mL) and water (1 mL), N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioc sabololan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (55 mg, 0.13 mmol), Cs₂CO₃ (110 mg, 0.34 mmol) and Pd(dppf)Cl₂ (8 mg, 0.01 mmol) was degassed and N₂3 times and then stirred at 100 ℃ for 16 hours. The reaction mixture was concentrated and purified by prep-HPLC (0.1% FA) to yield N-(4-methyl-3-(2-((2-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide formic acid (6.7 mg, 10.7% yield) was obtained as a yellow solid.

[1215] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.76 (s, 1H), 9.20 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 8.23 (dd, J = 5.2, 2.0 Hz, 1H), 8.09 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 8.4, 2.0 Hz, 1H), 7.25-7.21 (m, 2H), 7.19 (s, 1H), 4.02-3.98 (m, 2H), 3.95-3.91 (m, 2H) , 2.46 (s, 3H), 2.21 (s, 3H). LCMS (M+H ⁺ ) m/z: 557.5.

Example 210: N-(4-methyl-3-(2-((4-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 210) manufacturing

[1216] Step 1: Synthesis of 6-bromo-N-(4-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1217] LiHMDS (0.7 mL, 0.70 mmol) was added dropwise to a mixture of 4-methylpyridin-3-amine (76 mg, 0.70 mmol) in THF (5 mL) at -60 °C and the mixture was stirred at -60 °C for 0.5 hour. 6-Bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (200 mg, 0.64 mmol) was added to the mixture at -60°C and the mixture was stirred at room temperature for 16 hours. The reaction mixture was saturated with NH ₄ Cl. (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product which was purified by silica column chromatography (EA:PE=0% to 90%, DCM:MeOH=9:1) to obtain 6-bromo-N-(4-methylpyridin-3-yl)-8,9-dihydroimidazo[1’,2’:1,6]pyrido[2,3-d]pyridonium Midin-2-amine (60 mg, crude) was obtained as a yellow oil. LCMS (M+H ⁺ ) m/z: 358.9

[1218] Step 2: Synthesis of N-(4-methyl-3-(2-((4-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1219] 디옥산:H ₂ O(10:1) (5 mL) 중 6-브로모-N-(4-메틸피리딘-3-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d] 피리미딘-2-아민 (80 mg, 0.22mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (100 mg, 0.25 mmol), Cs ₂ CO ₃ (215 mg, 0.66 mmol) 및 Pd(dppf)Cl ₂ (16 mg, 0.022 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전한 다음, 110℃에서 16 시간 교반하였다. The reaction mixture was concentrated and purified by silica column chromatography (DCM:MeOH=10:1) to give the crude product which was further purified by trituration with EA:n-hexane (1:10) to obtain N-(4-methyl-3-(2-((4-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4 Obtained -(trifluoromethyl)picolinesulfonamide (9.1 mg, 7.3% yield) as a yellow oil.

[1220] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.79 (s, 1H), 9.39 (s, 1H), 9.04 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 8.41-8.38 (m, 1H), 8.34 (s, 1H), 8.25 (d, J = 4.4 Hz, 1H), 8.10 (d, J = 4.0 Hz, 1H), 7.86 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.29-7.26 (m, 3H), 4.11-4.03 (m, 2H), 3.93 (t, J = 8.8 Hz, 2H), 2.28 (s, 3H), 2.26 (s, 3H). LCMS (M+H ⁺ ) m/z: 557.1.

Example 211: N-(3-(2-((2,6-dimethylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 211) manufacturing

[1221] Step 1: Synthesis of 6-bromo-N-(2,6-dimethylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1222] A mixture of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, crude) and 2,6-dimethylpyridin-3-amine (73 mg, 0.56 mmol) in DMSO (5 mL) was stirred at 120°C for 16 hours. The reaction mixture was diluted with DCM (30 mL) and washed with brine (20 mL*2), then the combined organic phases were concentrated and purified by silica column chromatography (DCM:MeOH=10:1) and preparative-TLC (PE:EA=0:1) to yield 6-bromo-N-(2,6-dimethylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3 Obtained -d]pyrimidin-2-amine (60 mg, 50% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 371.0, 373.0.

[1223] Step 2: Synthesis of N-(3-(2-((2,6-dimethylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide formic acid

[1224] 디옥산 (10 mL) 및 물 (1 mL) 중 6-브로모-N-(2,6-디메틸피리딘-3-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (60 mg, 0.16 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (79 mg, 0.19 mmol), Cs ₂ CO ₃ (158 mg, 0.49 mmol) 및 Pd(dppf)Cl ₂ (15 mg, 0.05 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 ㅊ추충전한 다음 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated and purified by silica column chromatography (DCM:MeOH=10:1) first and then by preparative-HPLC (0.1% FA) to obtain N-(3-(2-((2,6-dimethylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)pyridine. Cholinesulfonamide formic acid (10.0 mg, 10.9 % yield) was obtained as a yellow solid.

[1225] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.75 (s, 1H), 9.14 (s, 1H), 9.03 (d, J=4.8 Hz, 1H), 8.33 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 8.09 (d, J=4.8 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.78-7.74 (m, 2H), 7.24 (d, J=8.4 Hz, 1H), 7.19 (s, 1H), 7.07 (d, J=8.4 Hz, 1H), 4.02-3.98 (m, 2H), 3.93-3.88 (m, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 2.21 (s, 3H). LCMS (M+H ⁺ ) m/z: 571.2.

Example 212: N-(4-methyl-3-(2-((2-methylpyridin-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 212) manufacturing

[1226] Step 1: Synthesis of 6-bromo-N-(2-methylpyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1227] To a mixture of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (200 mg, crude) in DMSO (5 mL) was added 2-methylpyridin-3-amine (41 mg, 0.10 mmol) and the mixture was stirred at 120°C for 16 hours. The mixture was aq. Diluted with NH ₄ Cl (20 mL) and extracted with DCM (30 mL x2). The combined organic phases were concentrated and purified by prep-TLC (DCM:MeOH=10:1) to afford 6-bromo-N-(2-methylpyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (31 mg, 13.6 % yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 357.1 and 359.1.

[1228] Step 2: Synthesis of N-(4-methyl-3-(2-((2-methylpyridin-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1229] 디옥산 (10 mL) 및 물 (1 mL) 중 6-브로모-N-(2-메틸피리딘-4-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (30 mg, 0.08 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (41 mg, 0.10 mmol), Cs ₂ CO ₃ (82 mg, 0.25 mmol) 및 Pd(dppf)Cl ₂ (6 mg, 0.05 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 ㅊ추충전하고, 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated and purified by silica column chromatography (DCM:MeOH=10:1) and then preparative-HPLC (0.1% FA) to obtain N-(4-methyl-3-(2-((2-methylpyridin-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6] pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfone The amide (2.3 mg, 4.9 % yield) was obtained as a yellow solid.

[1230] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (s, 1H), 10.18 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.47 (s, 1H), 8.33 (s, 1H), 8.25 (d, J = 5.6 Hz, 1H), 8.09 (d, J = 4.0 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H),7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.70 (s, 1H), 7.66 (d, J = 6.0 Hz, 1H), 7.29-7.25 (m, 2H), 4.22-4.18 (m, 2H), 4.03-3.98 (m, 2H), 2.42 (s, 3H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 557.8.

Example 213: N-(4-methyl-3-(2-((3-methylpyridin-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 213) manufacturing

[1231] Step 1: Synthesis of 6-bromo-N-(3-methylpyridin-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1232] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (80 mg, 0.26 mmol) in DMSO (2 mL) was added 3-methylpyridin-4-amine (33.5 mg, 0.310 mmol). The mixture was stirred at 120°C for 16 hours. The reaction mixture was purified by preparative-HPLC (0.1% NH ₃ .H ₂ O) to afford 6-bromo-N-(3-methylpyridin-4-yl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (30 mg, 26% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 357.1.

[1233] Step 2: Synthesis of N-(4-methyl-3-(2-((3-methylpyridin-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1234] 디옥산 (1.8 mL) 및 물 (0.2 mL) 중 6-브로모-N-(3-메틸피리딘-4-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (20 mg, 0.056 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (25 mg, 0.062 mmol), Cs ₂ CO ₃ (54.6 mg, 0.17 mmol) 및 Pd(dppf)Cl ₂ (4.1 mg, 0.0056 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전하고 110℃에서 2시간 교반하였다. The reaction mixture was concentrated and purified by silica column (DCM:MeOH= 10:1) followed by preparative-HPLC (0.1% FA) and preparative-TLC (DCM:MeOH= 10:1) N-(4-methyl-3-(2-((3-methylpyridin-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl )Phenyl)-4-(trifluoromethyl)picolinesulfonamide (2.9 mg, 6% yield) was obtained as a yellow solid.

[1235] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.79 (s, 1H), 9.15 (br, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.48 (s, 1H), 8.33-8.31 (m, 3H), 8.10 (d, J = 6.0 Hz, 1H), 8.02 (d, J = 5.6 Hz, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.4, 2.4 Hz, 1H), 7.35 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 4.16-4.14 (m, 2H), 3.97 (t, J = 9.6 Hz, 2H), 2.30 (s, 3H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 557.8.

Example 214: N-(4-methyl-3-(2-(pyridin-4-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 214) manufacturing

[1236] Step 1: Synthesis of 6-bromo-N- (pyridin-4-yl) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine

[1237] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 0.32 mmol) in DMSO (2 mL) was added pyridin-4-amine (36 mg, 0.38 mmol). The mixture was stirred at 120°C for 16 hours. The reaction mixture was purified by preparative-HPLC (0.1% NH ₃ .H ₂ O) to afford 6-bromo-N-(pyridin-4-yl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 36% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 343.1.

[1238] Step 2: Synthesis of N-(4-methyl-3-(2-(pyridin-4-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1239] 디옥산 (4 mL) 및 물 (0.5 mL) 중 6-브로모-N-(피리딘-4-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (30 mg, 0.087 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (39 mg, 0.096 mmol), Cs ₂ CO ₃ (85 mg, 0.26 mmol) 및 Pd(dppf)Cl ₂ (6.4 mg, 0.0087 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전한 다음, 110℃에서 2 시간 교반하였다. The reaction mixture was concentrated and purified by silica column chromatography (EA/PE 5% to 90% DCM:MeOH= 10:1) to give the crude product which was triturated with MeOH (5 mL) to N-(4-methyl-3-(2-(pyridin-4-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoro). Romethyl)picolinesulfonamide (13.4 mg, 21% yield) was obtained as a yellow solid.

[1240] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (s, 1H), 10.24 (s, 1H), 9.03 (d, J = 4.4 Hz, 1H), 8.45 (s, 1H), 8.38 (d, J = 5.2 Hz, 2H), 8.34 (s, 1H), 8.09 (d, J = 3.2 Hz, 1H), 7.87-7.79 (m, 4H), 7.27-7.25 (m, 2H), 4.19 (t, J = 9.2 Hz, 2H), 4.00 (t, J = 9.2 Hz, 2H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 543.4.

Example 215: N-(4-methyl-3-(2-(pyridin-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (Compound 215)

[1241] Step 1: Synthesis of 6-bromo-N-(2-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1242] To a mixture of pyridin-3-amine (30 mg, 0.32 mmol) in DMF (5 mL) was added NaH (16 mg, 0.38 mmol) at 0 °C and stirred for 0.5 h, then 6-bromo- 2-(Methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (106 mg, crude) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (DCM/MeOH=10:1) to obtain 6-bromo-N-(2-methylpyridin-3-yl)-8,9-dihydroimidazo[1' ,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 33% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 343.0, 345.0.

[1243] Step 2: Synthesis of N-(4-methyl-3-(2-(pyridin-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1244] (6-Bromo-N-(2-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 0.12 mmol) in dioxane (10 mL) and water (1 mL), N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxy sabololan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (57 mg, 0.14 mmol), Cs₂CO₃ (114 mg, 0.35 mmol) and Pd(dppf)Cl₂ (8 mg, 0.01 mmol) was degassed and N₂3 times and then stirred at 100 °C for 16 hours. The reaction mixture was concentrated and purified by prep-HPLC (0.1% FA) to afford N-(4-methyl-3-(2-(pyridin-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (2.8 mg, 4.4 % yield) as a yellow solid.

[1245] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.77 (s, 1H), 10.00 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.95 (d, J = 2.8 Hz, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.31-8.25 (m, 2H), 8.18 (dd, J = 4.8, 1.2 Hz, 1H), 8.08 (dd, J = 5.2, 1.2 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 8.4, 2.4 Hz, 1H), 7.35-7.32 (m, 1H), 7.26-7.23 (m, 2H), 4.14 (t, J = 9.6 Hz, 2H), 3.98 (t, J = 9.6 Hz, 2H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 543.4.

Example 216: N-(4-methyl-3-(2-(pyridin-2-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 216) manufacturing

[1246] The preparation of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide is described in Example 106.

[1247] Step 1: Synthesis of N-(4-methyl-3-(2-(pyridin-2-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1248] A mixture of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (120 mg, crude) and pyridin-2-amine (100 mg) in DMSO (0.5 mL) at 110°C Stirred for 16 hours. Water was added and the reaction mixture was extracted with EA. The pooled extracts were washed with brine. Concentrated and purified by flash (DCM: MeOH =10:1) and preparative-HPLC (NH ₄ HCO ₃ ) to yield N-(4-methyl-3-(2-(pyridin-2-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (5.0 mg) as yellow Obtained as a solid.

[1249] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.80 (s, 1H), 9.92 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.42 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H), 8.30 (d, J = 1.2 Hz, 1H), 8.1 0 (d, J = 5.2 Hz, 1H), 7.88-7.86 (m, 1H), 7.80-7.77 (m, 2H), 7.26-7.25 (m, 2H), 7.04-7.02 (m, 1H), 4.19-4.14 (m, 2H), 3.99-3.95 (m, 2H) ), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 543.0.

Example 217: N-(4-methyl-3-(2-(pyrazin-2-ylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 217) manufacturing

[1250] Step 1: Synthesis of 6-bromo-N-(pyrazin-2-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1251] To a solution of pyrazin-2-amine (61 mg 0.64 mmol) in dry THF (5 mL) was added NaH (32 mg, 0.80 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour, then 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 0.32 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with NH4Cl aq. and diluted with EA. The combined extracts were concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=10/1) to give 6-bromo-N-(pyrazin-2-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (35 mg, 31.8% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 344.1 and 346.1.

[1252] Step 2: N-(4-methyl-3-(2-(pyrazin-2-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1253] 디옥산 (5 mL) 및 물 (0.5 mL) 중 6-브로모-N-(피라진-2-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (45 mg, 0.131 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (58 mg, 0.144 mmol), Cs ₂ CO ₃ (128 mg, 0.392 mmol) 및 Pd(dppf)Cl ₂ (5 mg, 0.006 mmol)의 혼합물을 탈기하고, N ₂ 로 3회 충전한 다음 95℃에서 16 시간 교반하였다. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=10/1) to give the crude product which was triturated with MeOH (1 mL) to N-(4-methyl-3-(2-(pyrazin-2-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfone. The amide (15.3 mg, 13.1 % yield) was obtained as a yellow solid.

[1254] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.83 (s, 1H), 10.74 (s, 1H), 9.60 (s, 1H), 9.04 (d, J = 4.8 Hz, 1H), 8.74 (s, 1H), 8.41 (s, 1H), 8.34-8.32 (m, 2H), 8.10 (d, J = 4.8 Hz, 1H), 7.94 (s, 1H), 7.86-7.83 (m, 1H), 7.69-7.65 (m, 1H), 7.33 (d, J = 8.4 Hz, 1H), 4.42-4.40 (m, 2H), 4.03 (t, J = 9.6 Hz, 2H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 544.3.

Example 218: N-(3-(2-((3-chloropyridin-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 218) manufacturing

[1255] Step 1: Synthesis of 6-bromo-N-(3-chloropyridin-2-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1256] To a solution of 3-chloropyridin-2-amine (83 mg 0.64 mmol) in dry THF (5 mL) was added NaH (32 mg, 0.80 mmol) at 0 ° C and the mixture was stirred at 0 ° C for 1 hour, then 6-bromo-2- (methylsulfinyl) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine ( 100 mg, 0.32 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=15/1) to give the crude product which was purified by preparative-HPLC (0.1% NH ₃ -H ₂ O) to obtain 6-bromo-N-(3-chloropyridin-2-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (20 mg, 16.6% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 377.0 and 379.0.

[1257] Step 2: Synthesis of N-(3-(2-((3-chloropyridin-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide formic acid

[1258] 6-Bromo-N-(pyrazin-2-yl)-8,9-dihydroimidazo[1',2':1,6] in dioxane (5 mL) and water (0.5 mL) Pyrido[2,3-d]pyrimidin-2-amine (48 mg, 0.127 mmol), N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (57 mg, 0.140 mmol), Cs ₂ CO ₃ (125 mg, 0.381 mmol) and Pd(dppf)Cl ₂ (5 mg, 0.006 mmol) was degassed, charged with N ₂ three times and stirred at 95° C. for 16 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=10/1) to give the crude product, which was purified by pre-HPLC (0.1% FA) to N-(3-(2- ((3-chloropyridin-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)- Obtained 4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide formic acid (17.3 mg, 21. % yield) as a yellow solid.

⁽ s; = 8.0, 4.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.20 ( _s , 1H), 3.99–3.90 (m, 4H), 2.21 (s, 3H). LCMS (M+H ⁺ ) m/z: 577.3.

Example 219: N-(3-(2-((3-fluoropyridin-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 219) manufacturing

[1260] The preparation of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide is described in Example 106.

[1261] Step 1: Synthesis of N-(3-(2-((3-fluoropyridin-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[1262] N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (130 mg, 0.25 mmol), 3-fluoropyridin-4-amine (280 mg, 2 .54 mmol) was degassed, charged with N ₂ three times and stirred at 120 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% NH ₃ H ₂ O) to afford N-(3-(2-((3-fluoropyridin-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (5 mg, 4% yield) as a yellow solid. obtained.

[1263] ¹ H NMR (400 MHz, CD ₃ OD): δ 9.73 (br, 1H), 9.55-9.49 (m, 2H), 8.98 (br, 1H), 8.49-8.43 (m, 2H), 8.00-7.89 (m, 3H), 7.50 (d, J = 8.0 Hz , 1H), 7.33 (s, 1H), 5.08–4.94 (m, 2H), 4.40–4.37 (m, 2H), 2.35 (s, 3H). LCMS (M+H ⁺ ) m/z: 561.1.

Example 220: N-(3-(2-((3-fluoropyridin-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 220) manufacturing

[1264] Step 1: Synthesis of N-(3-(2-((3-fluoropyridin-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[1265] N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (100 mg, 0.20 mmol), 3-fluoropyridin-2-amine (219 mg, 2 .0 mmol) was degassed, charged with N ₂ three times, and stirred at 120° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% NH ₃ H ₂ O) to afford N-(3-(2-((3-fluoropyridin-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (15 mg, 14% yield) as yellow Obtained as a solid.

[1266] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.77 (s, 1H), 9.96 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 8.23 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 4.8 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.79-7.72 (m, 2H), 7.34-7.30 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.21 (s, 1H), 3.99-3.92 (m, 4H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 561.1.

Example 221: N-(3-(2-((6-methoxypyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 221) manufacturing

[1267] Step 1: Synthesis of N-(3-(2-((6-methoxypyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[1268] To a solution of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (70 mg, crude) in DMSO (8 drops) was added 6-methoxypyridin-3-amine (124 mg, 1 mmol). With the addition of JTek. The mixture was stirred at 80 °C for 3 hours. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by preparative-HPLC to obtain N-(3-(2-((6-methoxypyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4 -(Trifluoromethyl)picolinesulfonamide (18 mg) was obtained as a yellow solid.

[1269] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.79 (s, 1H), 9.79 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.60 (s, 1H), 8.36-8.33 (m, 2H), 8.09-8.06 (m, 2H), 7.86 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.28-7.22 (m, 2H), 6.81 (d, J = 9.2 Hz, 1H), 4.12 (t, J = 9.6 Hz, 2H), 3.96 (t, J = 9.6 Hz, 2H), 3.83 (s, 3H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 573.0.

Example 222: N-(3-(2-((2-methoxypyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (Compound 222)

[1270] Step 1: Synthesis of N-(3-(2-((2-methoxypyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[1271] To a mixture of N-(4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (50 mg, 0.1 mmol) in DCM (3 mL) was added m-CPBA (43 mg, 0.25 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction was concentrated and a solution of 2-methoxypyridin-3-amine (62 mg, 0.5 mmol) in DMSO (0.1 mL) was added to the reaction mixture. The reaction was stirred at 200 °C for 2 hours and purified by preparative-HPLC (0.5% FA) to obtain N-(3-(2-((2-methoxypyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (4.8 mg, 8 % yield) was obtained as a yellow solid.

[1272] ¹ H NMR (400 MHz, CD ₃ OD): δ 8.98 (d, J = 5.2 Hz, 1H), 8.77 (dd, J = 8.0, 1.2 Hz, 1H), 8.51 (s, 1H), 8.44 (s, 1H), 7.94 (d, J = 4.4 Hz, 1H), 7.85-7.82 (m, 2H), 7.76-7.75 (m, 1H), 7.47 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.04-7.01 (m, 1H), 4.64 (s, 1H), 4.42 (t, J = 9.6 Hz, 2H), 4.12-4.09 (m, 2H), 4.08 (s, 3H), 2.30 (s, 3H). LCMS (M+H ⁺ ) m/z: 573.0.

Example 223 and Example 224: N-(3-(2-((4-methoxypyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 223) Preparation and N-(3-(2-((4-hydroxypyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 224) manufacturing

[1273] Step 1: N-(3-(2-((4-methoxypyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide and N-(3-(2-((4-hydroxypyridin-3-yl)amino)-8,9 Synthesis of -dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[1274] To a mixture of N-(4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (50 mg, 0.1 mmol), m-CPBA (43 mg, 0.25 mmol) was added. The mixture was stirred at 25 °C for 0.5 h. The reaction was concentrated and a solution of 4-methoxypyridin-3-amine (62 mg, 0.5 mmol) in DMSO (0.5 mL) was added to the reaction mixture. The reaction was stirred at 25°C for 16 hours and purified by preparative-HPLC (NH4HCO3) to yield N-(3-(2-((4-methoxypyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (3.6 mg) as yellow Obtained as a solid. And N-(3-(2-((4-hydroxypyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (2.5 mg) was obtained as a yellow solid.

[1275] 화합물 223:1H NMR (400 MHz, CD ₃ OD): δ 9.43 (dd, J = 7.6, 2.0 Hz, 1H), 9.33 (d, J = 2.0 Hz, 1H), 8.99 (d, J = 5.2 Hz, 1H), 8.77 (s, 1H), 8.50 (br, 1H), 8.44 (s, 1H), 7.95 (d, J = 4.0 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.75 (dd, J = 8.4, 2.4 Hz,1H), 7.60 (d, J = 7.2 Hz, 1H), 7.53 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 4.43 (t, J = 9.6 Hz, 2H), 4.32 (s, 3H), 4.19 (t, J = 9.6 Hz, 2H), 2.32 (s, 3H). LCMS (M+H ⁺ ) m/z: 573.0.

[1276] 화합물 224: ¹ H NMR (400 MHz, CD ₃ OD): δ 8.99-8.97 (m, 2H), 8.75 (d, J = 2.0 Hz, 1H), 8.66 (s, 1H), 8.44 (s, 1H), 7.94 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 8.0, 2.0 Hz, 1H), 7.47 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 8.0 Hz, 1H), 4.41 (t, J = 9.6 Hz, 2H), 4.14 (t, J = 9.6 Hz, 2H), 2.32 (s, 3H). LCMS (M+H ⁺ ) m/z: 559.0.

Example 225: N-(3-(2-((2-fluorophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 225) manufacturing

[1277] Step 1: Synthesis of 6-bromo-N-(2-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1278] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 0.32 mmol) in DMSO (5 mL) was added 2-fluoroaniline (71 mg, 0.72 mmol). The reaction mixture was stirred at 120° C. for 16 hours. The reaction mixture was diluted with EA (30 mL), washed with water (10 mL x 3), brine (10 mL x 3), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with EA (8 mL) and filtered to give 6-bromo-N-(2-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (33 mg, 29% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 361.9.

[1279] Step 2: Synthesis of N-(3-(2-((2-fluorophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[ ₁₂₈₀ ] N-(4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (39 mg, 0.096 mmol), Pd(dppf)Cl ₂ (6.7 mg, 0.009 mmol), Cs ₂ CO ₃ (89 mg, 0.27 mmol) were added. The mixture was stirred at 110° C. for 1.5 h under N ₂ . The reaction mixture was diluted with EA (25 mL) then washed with H ₂ O (10 mL x 3), brine (10 mL x 3). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (EA=100%) to give N-(3-(2-((2-fluorophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (22.2 mg, 44% yield) as a pale yellow solid.

[1281] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.76 (s, 1H), 9.27 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 8.32 (s, 1H), 8.09-8.08 (m, 1H), 7.84–7.84 (m, 2H), 7.79–7.64 (m, 1H), 7.25–7.16 (m, 5H), 4.06–4.02 (m, 2H), 3.95–3.90 (m, 2H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 560.4.

Example 226: N-(3-(2-((3-fluorophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 226) manufacturing

[1282] Step 1: Synthesis of 6-bromo-N-(3-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1283] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 0.32 mmol) in DMSO (5 mL) was added 3-fluoroaniline (53 mg, 0.48 mmol). The reaction mixture was stirred at 120° C. for 16 hours. The reaction mixture was diluted with EA (30 mL). The organic layer was washed with aq. Washed with NH ₄ Cl (10 mL x 3) and brine (10 mL x 3), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with EA (5 mL) and filtered to give 6-bromo-N-(3-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (53 mg, 46% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 359.9 and 361.9.

[1284] Step 2: N-(3-(2-((3-fluorophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[ ₁₂₈₅ ] N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa Borolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (63 mg, 0.15 mmol), Pd(dppf)Cl ₂ (11 mg, 0.014 mmol), Cs ₂ CO ₃ (144 mg, 0.44 mmol) were added and the mixture was stirred at 110 °C for 1.5 h under N ₂ . The reaction mixture was diluted with EA (30 mL). The organic phase was washed with H ₂ O (10 mL x 2) and brine (10 mL x 2), dried with Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (EA=100%) and then triturated with EA (5 mL) to give N-(3-(2-((3-fluorophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (8.6 mg, 11% yield) as yellow Obtained as a solid.

^{[1286] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 10.77 (s, 1H), 10.05 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 8.09 (d, J = 3.6 Hz, 1H), 7.91-7.86 (m, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.33-7.31 (m, 1H), 7.26-7.24 (m, 2H), 6.80-6.76 (m, 1H), 4.18-4.12 (m, 2H), 4.00-3.96 (m, 2H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 560.4.

Example 227: N-(3-(2-((4-fluorophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 227) manufacturing

[1287] Step 1: Synthesis of 6-bromo-N-(4-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1288] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (113 mg, 0.36 mmol) in DMSO (5 mL) was added 4-fluoroaniline (80 mg, 0.72 mmol). The reaction mixture was stirred at 125 °C for 1 hour. The reaction mixture was diluted with EA (30 mL). The organic layer was washed with water (10 mL x 3), brine (10 mL x 3), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with EA (10 mL) and filtered to give 6-bromo-N-(4-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (67 mg, 51% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 360.0 and 362.0.

[1289] Step 2: Synthesis of N-(3-(2-((4-fluorophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[1290] 디옥산/H ₂ O (7 mL/3 mL) 중 6-브로모-N-(4-플루오로페닐)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘 -2-아민 (67 mg, 0.186 mmol)의 혼합물에 N-(4-메틸-3- (4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (83 mg, 0.205 mmol), Pd(dppf)Cl ₂ (14 mg, 0.0186 mmol), Cs ₂ CO ₃ (181 mg, 0.558 mmol)를 첨가하였다. The mixture was stirred at 120 °C for 2 h under N ₂ . The reaction mixture was diluted with EA (30 mL). The organic layer was washed with H ₂ O (10 mL x 3), brine (10 mL x 3), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (EA=100%) to give N-(3-(2-((4-fluorophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (43.1 mg, 41% yield) as a yellow solid.

[1291] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.77 (s, 1H), 9.89 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 8.09 (d, J = 4.4 Hz, 1H), 7.86-7.82 (m, 3H), 7.77 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 4.17-4.13 (m, 2H), 3.99-3.95 (m, 2H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 560.5.

Example 228: N-(3-(2-((3-fluoro-4-methylphenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 228) manufacturing

[1292] Step 1: Synthesis of 6-bromo-N-(3-fluoro-4-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-2-amine

[1293] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (113 mg, 0.36 mmol) in DMSO (5 mL) was added 3-fluoroaniline (90 mg, 0.72 mmol). The reaction mixture was stirred at 125 °C for 2 hours. The reaction mixture was diluted with EA (30 mL), washed with water (10 mL x 3), brine (10 mL x 3), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with EA (10 mL) to give 6-bromo-N-(3-fluoro-4-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-2-amine (67 mg, 50% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 374.0 and 376.0.

[1294] Step 2: Synthesis of N-(3-(2-((3-fluoro-4-methylphenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[ ₁₂₉₅ ] N-(4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxy Saborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (79 mg, 0.196 mmol), Pd(dppf)Cl ₂ (13 mg, 0.018 mmol), Cs ₂ CO ₃ (173 mg, 0.534 mmol) were added and the mixture was stirred at 120 °C for 2 h under N ₂ . The reaction mixture was diluted with EA (30 mL). The organic layer was washed with H ₂ O (10 mL x 3), brine (10 mL x 3), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (EA=100%) and then triturated with MeOH (3 mL) to give N-(3-(2-((3-fluoro-4-methylphenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (15.2 mg, 15% yield) was obtained as a yellow solid.

^{[1296] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 10.77 (s, 1H), 9.93 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.39 (s, 1H), 8.34 (s, 1H), 8.09 (dd, J = 5.2, 1.2 Hz, 1H), 7.86-7.77 (m, 3H), 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 7.26-7.15 (m, 3H), 4.14 (t, J = 9.6 Hz, 2H), 3.98 (t, J = 9.6 Hz, 2H), 2.23 (s, 3H), 2.18 (s, 3H). LCMS (M+H ⁺ ) m/z: 574.4.

Example 229: N-(3-(2-((3-(hydroxymethyl)phenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 229) manufacturing

[1297] Step 1: Synthesis of (3-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl) methanol

[1298] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (crude, 432 mg, 0.68 mmol) in DMSO (10 mL) was added (3-aminophenyl)methanol (125 mg, 1.02 mmol). The mixture was stirred at 120° C. for 16 hours. The reaction was cooled to room temperature, diluted with water (50 mL), and the reaction mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by trituration with EA (5.0 mL) to afford (3-((6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)methanol (200 mg, 79% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 372.0 and 374.0.

[1299] Step 2: N-(3-(2-((3-(hydroxymethyl)phenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[ Synthesis of 2,3-d] pyrimidin-6-yl) -4-methylphenyl) -4- (trifluoromethyl) picolinesulfonamide formic acid

[1300] 디옥산 (10 mL) 및 물 (1 mL) 중 (3-((6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)아미노)페닐)메탄올 (150 mg, 0.40 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (195 mg, 0.48 mmol), Cs ₂ CO ₃ (395 mg, 1.21 mmol) 및 Pd(dppf)Cl ₂ (15 mg, 0.02 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전한 다음 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated and purified by prep-HPLC (0.1% FA) to afford N-(3-(2-((3-(hydroxymethyl)phenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide formic acid (29.7 mg, 13% yield) as a yellow solid. obtained.

^{[1301] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 10.79 (s, 1H), 9.96 (br, 1H), 9.04 (d, J = 5.2 Hz, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 8.09 (d, J=4.8 Hz, 1H), 7.89 (s, 2H), 7.80 (dd, J = 8.4, 2.4 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.39-7.35 (m, 1H), 7.29-7.24 (m, 2H), 6.96 (d, J = 7.6 Hz, 1H), 5.17-5.15 (m, 1H), 4.9 (d, J = 3.2 Hz, 2H), 4.26-4.21 (m, 2H), 3.99 (t, J = 9.6 Hz, 2H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 572.5.

Example 230: N-(4-methyl-3-(2-((pyridin-3-ylmethyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinsulfonamide e (compound 230) manufacturing

[1302] Step 1: Synthesis of 6-bromo-N-(pyridin-3-ylmethyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1303] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidine (crude, 50 mg, 0.16 mmol) in DMSO (5 mL) was added pyridin-3-ylmethanamine (35 mg, 0.32 mmol). The mixture was stirred at 120° C. for 16 hours. The reaction was cooled to room temperature and purified by prep-HPLC (0.1% NH ₃ -H ₂ O) to give 6-bromo-N-(pyridin-3-ylmethyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 70% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 357.0 and 359.0.

[1304] Step 2: Synthesis of N-(4-methyl-3-(2-((pyridin-3-ylmethyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1305] 디옥산 (5 mL) 및 물 (0.5 mL) 중 6-브로모-N-(피리딘-3-일메틸)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (40 mg, 0.108 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (48 mg, 0.118 mmol), Cs ₂ CO ₃ (105 mg, 0.323 mmol) 및 Pd(dppf)Cl ₂ (4 mg, 0.005 mmol)의 혼합물을 N ₂ 로 3회 충전한 다음 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=10/1) to give the crude product which was purified by preparative-HPLC (0.1% NH ₃ -H ₂ O) to obtain N-(4-methyl-3-(2-((pyridin-3-ylmethyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl) Phenyl)-4-(trifluoromethyl)picolinesulfonamide (10.0 mg, 22.8 % yield) was obtained as a yellow solid.

[1306] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.74 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.61-8.59 (m, 1H), 8.44 (d, J = 4.0 Hz, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 8.13-8.08 (m, 2H), 7.79-7.71 (m, 3H), 7.35 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 4.53 (s, 2H), 4.01 (t, J = 8.4 Hz, 2H), 3.90 (t, J = 8.4 Hz, 2H), 2.19 (s, 3H). LCMS (M+H ⁺ ) m/z: 557.3.

Example 231: N-(4-methyl-3-(2-((2-methylthiazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 231) manufacturing

[1307] Step 1: Synthesis of N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-2-methylthiazol-5-amine

[1308] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (500 mg, 1.60 mmol) in DMSO (30 mL) was added 2-methylthiazol-5-amine (273 mg, 2.40 mmol) and the mixture was stirred at 120 °C for 2 hours. The reaction mixture was removed in vacuo. The residue was purified by column chromatography (DCM:MeOH=20:1) to give N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-2-methylthiazol-5-amine (250 mg, 39.2% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 363.1 and 365.1.

[1309] Step 2: Synthesis of N-(4-methyl-3-(2-((2-methylthiazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[ ₁₃₁₀ ] N-(4-methyl-3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (224 mg, 0.55 mmol), Pd(dppf)Cl ₂ (40 mg, 0.055 mmol), Cs ₂ CO ₃ (539 mg, 1.65 mmol) were added and the mixture was stirred at 100 °C for 3 h under N ₂ . The reaction mixture was concentrated and purified by prep-HPLC (0.1% NH ₃ H ₂ O) to obtain N-(4-methyl-3-(2-((2-methylthiazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (63.2 mg, 20.4% aqueous rate) was obtained as a yellow solid.

^{[1311] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 12.07 (br, 1H), 10.94 (s, 1H), 10.12 (s, 1H), 9.11 (s, 1H), 9.05 (d, J = 4.8 Hz, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.12 (d, J = 4.4 Hz, 1H), 8.04 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.82 (t, J = 9.2 Hz, 2H), 4.14 (t, J = 9.2 Hz, 2H), 2.67 (s, 3H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 563.3.

Example 232: N-(4-methyl-3-(2-((5-methylthiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 232) manufacturing

[1312] The preparation of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide is described in Example 106.

[1313] Step 1: Synthesis of N-(4-methyl-3-(2-((5-methylthiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1314] N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinsulfonamide (150 mg, crude), DIEA (0.3 mL) and 5-methylthiazol-2-amine (100 mg) in DMSO (1 mL) ) was stirred at 100 °C for 1 hour. The mixture was purified by preparative-HPLC (0.1% FA) to give N-(4-methyl-3-(2-((5-methylthiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (6.4 mg) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 11.64 (s, 1H), 10.79 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 8.10 (dd, J = 5.2, 1.2 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.28-7.25 (m, 2H), 7.12 (d, J = 1.2 Hz, 1H), 4.26-4.21 (m, 2H), 4.04-3.99 (m, 2H), 2.36 (s, 3H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 562.9.

Example 233: N-(4-methyl-3-(2-((4-methylthiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 233) manufacturing

[1315] Step 1: Synthesis of N-(4-methyl-3-(2-((4-methylthiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1316] To a solution of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (100 mg, crude) in DMSO (8 drops) was added 4-methylthiazol-2-amine (342 mg, 3 mmol). did The mixture was stirred at 80 °C for 3 hours. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by prep-HPLC to obtain N-(4-methyl-3-(2-((4-methylthiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4- (Trifluoromethyl)picolinesulfonamide (3.2 mg, 4% yield) was obtained as a yellow solid.

[1317] 1H NMR (400 MHz, DMSO-d6): δ 11.76 (br s, 1H), 10.78 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.47 (s, 1H), 8.33 (s, 1H), 8.09 (d, J = 3.6 Hz, 1 H), 7.87 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.31 (br, 1H), 7.26 (d, J = 8.4 Hz, 2H), 6.73 (s, 1H), 4.26-4.23 (m, 2H), 4.00 (t, J = 9.2 Hz, 2H), 2.27 (s, 3H), 2.23 (s, 3H).

Example 234: N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 234) manufacturing

[1318] Step 1: Synthesis of 6-bromo-N-(1-methyl-1H-pyrazol-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1319] To a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (5.5 g, 17.5 mmol) in DMSO (20 mL) was added 1-methyl-1H-pyrazol-3-amine (3.4 g, 35 mmol). The resulting mixture was stirred at 120°C for 16 hours. The reaction mixture was cooled and filtered to give 6-bromo-N-(1-methyl-1H-pyrazol-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (4 g, 67% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 346.1 and 381.1.

[1320] Step 2: Synthesis of N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinsulfonamide hydrochloride

[1321] 6-bromo-N-(1-methyl-1H _- pyrazol-3-yl)-8,9-dihydroimidazo[ N-(4-methyl-3-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (4.7 g, 11.6 mmol), Pd(dppf)Cl ₂ (850 mg, 1.16 mmol), Cs ₂ CO ₃ (11.3 g, 34.8 mmol) were added. The mixture was degassed 3 times, charged with N ₂ and stirred at 110° C. for 5 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography (DCM/MeOH=10/1) to give the crude product which was then triturated twice with EA (200 mL) to obtain N-(4-methyl-3-(2-( (1-methyl-1H-pyrazol-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6- Obtained yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide hydrochloride (4494 mg, 71% yield) as a yellow solid.

[1322] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.02 (s, 1H), 10.93 (s, 1H), 9.97 (s, 1H), 9.06-9.05 (m, 2H), 8.34 (s , 1H), 8.23 (s, 1H), 8.12-8.11 (m, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 8.4, 2.0 Hz, 1H), 7.71 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.81 (s, 1H), 4.73 (t, J = 9.6 Hz, 2H), 4.07 (t, J = 10.0 Hz, 2H), 3.81 (s, 3H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 546.3.

Example 235: N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 235) manufacturing

[1323] Step 1: Synthesis of N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1324] To a mixture of N-(4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (100 mg, 0.2 mmol) in DCM (10 mL) was added m-CPBA (86 mg, 0.5 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction was concentrated and a solution of 1-methyl-1H-pyrazol-5-amine (97 mg, 1.0 mmol) in DMSO (0.5 mL) was added. The reaction mixture was stirred at 100 °C for 5 hours and then purified by flash (DCM: MeOH = 10:1) and preparative-HPLC (0.5% FA) to N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4- (Trifluoromethyl)picolinesulfonamide (6.8 mg, 6% yield) was obtained as a yellow solid.

[1325] ^1H NMR (400 MHz, CD ₃ OD): δ 8.99 (d, J = 4.8 Hz, 1H), 8.82 (d, J = 4.0 Hz, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 8.37 (s, 1H), 7.95 (d, J = 4.0 Hz; Hz, 2H), 4.17–4.12 (m, 5H), 2.32 (s, 3H). LCMS (M+H ⁺ ) m/z: 546.0.

Example 236: N-(3-(2-((1,3-dimethyl-1H-pyrazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 236) manufacturing

[1326] Step 1: Synthesis of 6-bromo-N-(1,3-dimethyl-1H-pyrazol-5-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1327] To a mixture of 1,3-dimethyl-1H-pyrazol-5-amine (112 mg, 1.01 mmol) in dry DMF (6.0 mL) was added NaH (54 mg, 1.34 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 0.5 hours, 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (210 mg, 0.67 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with water and extracted with DCM (50 mL x3). The combined organic phases were washed with brine, dried over Na2SO4 and filtered. The residue was purified by column chromatography (DCM/MeOH=10/1) to give the crude product which was triturated with EA/PE (1/1, 2.0 mL) to obtain 6-bromo-N-(1,3-dimethyl-1H-pyrazol-5-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (12 mg, 5% aqueous rate) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 358.0 and 360.0.

[1328] Step 2: Synthesis of N-(3-(2-((1,3-dimethyl-1H-pyrazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide hydrogen chloride

[1329] 디옥산 (1.0 mL) 및 H2O (0.1 mL) 중 6-브로모-N-(1,3-디메틸-1H-피라졸-5-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (10 mg, 0.03 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (13.5 mg, 0.033 mmol), Cs2CO3 (19.6 mg, 0.06 mmol) 및 Pd(dppf)Cl ₂ (2.3 mg, 0.003 mmol)의 혼합물을 탈기하고, N ₂ 로 3회 충전한 다음 90℃에서 3시간 교반하였다. The reaction mixture was concentrated and purified by preparative-TLC (DCM/MeOH=10/1) and preparative-HPLC (0.1%HCl) to N-(3-(2-((1,3-dimethyl-1H-pyrazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoro Romethyl)picolinesulfonamide hydrogen chloride (0.96 mg, 6.1% yield) was obtained as a yellow solid.

^{[1330] 1} H NMR (400 MHz, CD ₃ OD): δ 9.04 (s, 1H), 8.97 (d, J = 4.8 Hz, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 7.95-7.93 (m, 2H), 7.79 (dd, J = 8.4, 2.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.43 (s, 1H), 4.77-4.72 (m, 2H), 4.17 (t, J = 10.0 Hz, 2H), 3.79 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H). LCMS (M+H ⁺ ) m/z: 560.3.

Example 237: N-(4-methyl-3-(2-((1-methyl-1H-1,2,3-triazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 237) manufacturing

[1331] Step 1: Synthesis of N-(4-methyl-3-(2-((1-methyl-1H-1,2,3-triazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1332] N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (51 mg, 0.1 mmol), 1-methyl-1H-1,2,3-triazol-4-amine in DMSO (0.2 mL) (98 mg, 1.0 mmol) was stirred at 100 °C for 1 hour. The reaction was purified by flash (DCM: MeOH=10:1) and prep-HPLC (0.5%FA) to obtain N-(4-methyl-3-(2-((1-methyl-1H-1,2,3-triazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl) Acquired picolinesulfonamide (5.4 mg, 10% yield) as a yellow solid.

[1333] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.79 (s, 1H),10.56 (s, 1H), 9.04 (d, J = 5.2 Hz, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.17-8.16 (m, 1H), 8.09 (dd, J = 5.2, 1.2 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.26-7.24 (m, 2H), 4.20-4.19 (m, 2H), 4.07 (s, 3H), 4.00-3.96 (m, 2H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 547.0.

Example 238: N-(4-methyl-3-(2-((1-methyl-1H-1,2,4-triazol-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 238) manufacturing

[1334] Step 1: Synthesis of 6-bromo-N-(1-methyl-1H-1,2,4-triazol-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1335] To a solution of 1-methyl-1H-1,2,4-triazol-3-amine (150 mg, 1.53 mmol) in DMF (6 mL) was added NaH (123 mg, 3.07 mmol, 60%wt in mineral oil). The reaction mixture was stirred at room temperature under N ₂ for 1 hour. Then a solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (300 mg, 0.96 mmol) in DMF (18 mL) was added dropwise to the above reaction solution. The resulting solution was stirred at room temperature under N ₂ for 1 hour, then quenched with saturated NH ₄ Cl and adjusted to pH 6.0 with 1M HCl. The solution was concentrated and the residue was triturated with DCM/MeOH =5/1 (10 mL). The filtrate was concentrated and purified by flash chromatography to give 6-bromo-N-(1-methyl-1H-1,2,4-triazol-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (20 mg, 6% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 349.0.

[1336] Step 2: Synthesis of N-(4-methyl-3-(2-((1-methyl-1H-1,2,4-triazol-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide formate

[1337] 디옥산 (4 mL) 및 물 (1 mL) 중 6-브로모-N-(1-메틸-1H-1,2,4-트리아졸-3-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (20 mg, 0.058 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (47 mg, 0.116 mmol), Cs ₂ CO ₃ (57 mg, 0.174 mmol) 및 Pd(dppf)Cl ₂ (13 mg, 0.0174 mmol)의 혼합물을 105℃에서 N ₂ 하에 2시간 교반하였다. The reaction mixture was cooled to room temperature and purified directly by flash chromatography to give the crude product. The crude product was purified by preparative-HPLC (0.1%/FA/CH ₃ CN/H ₂ O) to yield N-(4-methyl-3-(2-((1-methyl-1H-1,2,4-triazol-3-yl)amino)-8,9-dihydroimidazo[1’,2’:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)py Cholinesulfonamide formate (2.54 mg, 7% yield) was obtained as a yellow solid.

^{[1338] 1} H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.73 (s, 1H), 9.03 (d, J = 4.4 Hz, 1H), 8.33-8.28 (m, 4H), 8.08 (d, J = 4.0 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.19 (s, 1H), 4.03-3.96 (m, 2H), 3.94-3.90 (m, 2H), 3.82 (s, 3H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z:547.1

Example 239: N-(3-(2-((1H-tetrazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 239) manufacturing

[1339] Step 1: Synthesis of N-(3-(2-((1H-tetrazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[1340] To a solution of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (70 mg, crude) in DMSO (8 drops) is added 1H-tetrazol-5-amine (170 mg, 2 mmol) did The mixture was stirred at 110 °C for 1 hour. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by preparative-HPLC to obtain N-(3-(2-((1H-tetrazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4 -(trifluoromethyl)picolinesulfonamide (10.2 mg) was obtained as a yellow solid.

[1341] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.55 (br, 1H), 10.83 (s, 1H), 9.04 (d, J = 4.8 Hz, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 8.10 (d, J = 5.2 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.4, 2.0 Hz, 1H), 7.49 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.23 (d, J = 9.6 Hz, 2H), 3.98 (t, J = 9.6 Hz, 2H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 533.9.

Example 240 and 241: N-(3-(2-((1H-pyrazol-5-yl)amino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (Compound 240) and N-(3-(2-(5-amino-1H-pyrazole) -1-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 241) manufacturing

[1342] Step 1: N-(3-(2-((1H-pyrazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide and N-(3-(2-(5-amino-1H-pyrazol-1-yl)-8,9 Synthesis of -dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[1343] N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (128 mg, 0.4 mmol, crude), 1H-pyrazol-5-amine (332 mg) in DMSO (0.2 mL) , 4.0 mmol) at 100°C for 2 hours, and the reaction mixture was purified by flash (DCM: MeOH=10:1) to N-(3-(2-((1H-pyrazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinsulfonamide. (12.5 mg), and N-(3-(2-(5-amino-1H-pyrazol-1-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (7.3 mg).

[1344] 화합물 241: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.80 (s, 1H), 9.04 (d, J = 5.2 Hz, 1H), 8.51 (s, 1H), 8.35-8.33 (m, 2H), 8.10-8.08 (m, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 8.0, 2.0 Hz, 1H), 7.34 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 5.89 (s, 1H), 5.51 (s, 2H), 4.15 (t, J = 9.2 Hz, 2H), 3.98 (t, J = 9.2 Hz, 2H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 531.9.

[1345] 화합물 240: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (s, 1H), 10.07 (s, 1H), 9.04 (d, J = 4.8 Hz, 1H), 8.37 (s, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 8.09 (dd, J = 4.8, 1.2 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 8.0, 2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.26-7.24 (m, 2H), 6.68 (br s, 1H), 4.16 (t, J = 9.6 Hz, 2H), 3.95 (t, J = 9.6 Hz, 2H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 532.0.

Example 242: N-(4-methyl-3-(2-((3-methylisothiazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 242) manufacturing

[1346] Step 1: Synthesis of N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-3-methylisothiazol-5-amine

[1347] To a solution of 3-methylisothiazol-5-amine hydrochloride (216 mg, 1.44 mmol) in DMF (18 mL) was added NaH (174 mg, 4.32 mmol). The reaction mixture was stirred at room temperature under N2 for 1 hour. A solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (450 mg, 1.44 mmol) in DMF (18 mL) was then added dropwise to the above reaction solution. The resulting solution was stirred at room temperature under N2 for 1 hour. The solution was directly purified by flash chromatography (0.1%/HCl/CHCN/H2O) to give N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-3-methylisothiazol-5-amine (170 mg, 29.7% yield). LCMS (M+H+) m/z: 363.0.

[1348] Step 2: Synthesis of N-(4-methyl-3-(2-((3-methylisothiazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide hydrochloride

[1349] N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-3-methylisothiazol-5-amine (170 mg, 0.43 mmol) in dioxane (10 mL) and water (2.5 mL), N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3, A mixture of 2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (159 mg, 0.39 mmol), Cs2CO3 (419 mg, 1.29 mmol) and Pd(dppf)Cl2 (63 mg, 0.086 mmol) was stirred at 100° C. under N2 for 2 h. The reaction mixture was cooled to room temperature and purified by prep-HPLC (0.1%/HCl/CHCN/H2O) to N-(4-methyl-3-(2-((3-methylisothiazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinsulfonamide hydrochloride (12 1 mg, 47% yield) as a yellow solid.

[1350] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.49 (s, 1H), 10.95 (s, 1H), 10.18 (s, 1H), 9.18 (s, 1H), 9.05 (d, J = 4.8 Hz, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.12 (d, J = 4.8 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 8.4, 2.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.92 (s, 1H), 4.87 (t, J = 10.0 Hz, 2H), 4.15 (t, J = 10.0 Hz, 2H), 2.36 (s, 3H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 563.0.

Example 243: N-(3-(2-(isothiazol-4-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 243) manufacturing

[1351] Step 1: N-(3-(2-hydroxy-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6- Synthesis of yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[1352] NaOH solution (11.7 mL, 11.7 mmol, 1M in water) was added. The solution was stirred 0.5 h at room temperature. The reaction mixture was purified by flash chromatography (0.1%/HCl/CH ₃ CN/H ₂ O) to afford N-(3-(2-hydroxy-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (900 mg, 46% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 467.1

[1353] Step 2: Synthesis of N-(3-(2-chloro-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[1354] A solution of N-(3-(2-hydroxy-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (1.3 g, crude, 2.8 mmol) in POCl ₃ (20 mL) was stirred at 110°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (0.1%/HCl/CH ₃ CN/H ₂ O) to afford N-(3-(2-chloro-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (220 mg, 16% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 485.2

[1355] Step 3: Synthesis of N-(3-(2-(isothiazol-4-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide hydrochloride

[1356] N-(3-(2-chloro-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (200 mg, 0.412 mmol), iso in i-PrOH (32 mL) and HCl/dioxane (8 drops, 4 M in dioxane) A solution of thiazol-4-amine hydrochloride (112 mg, 0.824 mmol) was stirred at 110° C. in a sealed test tube for 2 hours. The residue was purified by preparative-HPLC (0.1%/HCl/CH ₃ CN/H ₂ O) to obtain N-(3-(2-(isothiazol-4-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide hydrochloride (107 mg, 44 % yield) was obtained as a yellow solid.

^{[1357] 1} H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 10.94 (s, 1H), 10.05 (s, 1H), 9.20 (s, 1H), 9.12 (s, 1H), 9.05 (d, J = 4.8 Hz, 1H), 8.82 (s, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.12 (d, J = 4.4 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.84-4.80 (m, 2H), 4.14-4.10 (m, 2H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 549.1

Example 244 N-(4-methyl-3-(8-((1-methyl-1H-imidazol-2-yl)amino)-1,2-dihydroimidazo[1,2-a][1,6]naphthyridin-4-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 244) manufacturing

[1358] Step 1: Synthesis of 1-methyl-2-nitro-1H-imidazole

[1359] To a solution of 2-nitro-1H-imidazole (1 g, 8.84 mmol) in DMF (40 mL) was added NaH (707 mg, 17.68 mmol, 60% wt in mineral oil). The mixture was stirred at room temperature under N2 for 1 hour. Then iodomethane (1.95 g, 13.26 mmol) was added. The mixture was stirred at room temperature under N2 for 15 minutes. The reaction mixture was quenched with saturated NH ₄ Cl (100 mL) and water (100 mL). The reaction mixture was extracted with EA (100 mL x 2). The combined organic phases were concentrated. The residue was purified by flash chromatography to give 1-methyl-2-nitro-1H-imidazole (600 mg, 53% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 128.0.

[1360] Step 2: Synthesis of 1-methyl-1H-imidazol-2-amine

[1361] To a solution of 1-methyl-2-nitro-1H-imidazole (620 mg, 4.88 mmol) in MeOH (20 mL) was added Pd/C (124 mg, 20% wt). The mixture was stirred at 50° C. under a H2 balloon for 6 hours. The mixture was filtered and the filtrate was concentrated to give 1-methyl-1H-imidazol-2-amine (400 mg, 84 % yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.45 (d, J = 1.2 Hz, 1H), 6.31 (d, J = 1.2 Hz, 1H), 5.21 (s, 2H), 3.29 (s, 3H).

[1362] Step 3: Synthesis of N-(4-methyl-3-(8-((1-methyl-1H-imidazol-2-yl)amino)-1,2-dihydroimidazo[1,2-a][1,6]naphthyridin-4-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1363] N-(3-(2-chloro-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (50 mg, 0.103 mmol), 1-methyl-1H-imidazol-2-amine (30 mg, 0.3 09 mmol) and DIEA (133 mg, 1.03 mmol) were stirred at 110 °C for 8 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative-HPLC (0.1%/TFA/CH ₃ CN/H ₂ O) to yield N-(4-methyl-3-(8-((1-methyl-1H-imidazol-2-yl)amino)-1,2-dihydroimidazo[1,2-a][1,6]naphthyridin-4-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide TFA salt (16 mg, 20% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.22 (s, 1H), 10.96 (s, 1H), 10.22 (s, 1H), 9.18 (s, 1H), 9.06 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.12 (dd, J = 5.0, 1.2 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.93 (dd, J = 8.0, 2.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 6.45 (s, 1H), 4.80 (t, J = 9.6 Hz, 2H), 4.14 (t, J = 10.4 Hz, 2H), 2.27 (s, 3H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 546.1.

Example 245: N-(3-(2-(isoxazol-4-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 245) manufacturing

[1364] Step 1: Synthesis of N-(3-(2-(isoxazol-4-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide hydrochloride

[1365] N-(3-(2-chloro-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (240 mg, 0.494 mmol) in i-PrOH (40 mL) and HCl/dioxane (6 drops, 4 M in dioxane), A solution of sazol-4-amine (166 mg, 1.976 mmol) was stirred at 110° C. in a sealed test tube for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative-HPLC (0.1%/HCl/CH ₃ CN/H ₂ O) to give N-(3-(2-(isoxazol-4-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (106 mg, 38.3 % yield) was obtained as a yellow solid.

[1366] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.96 (s, 1H), 10.93 (s, 1H), 10.05 (s, 1H), 9.33 (s, 1H), 9.09 (s, 1H), 9.05 (d, J = 4.8 Hz, 1H), 8.80 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.12 (t, J = 5.2 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 8.4, 2.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.87 (t, J = 10.0 Hz, 2H), 4.10 (t, J = 10.0 Hz, 2H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 533.5.

Example 246: Preparation of N-(4-methyl-3-(2-((3-methylisoxazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1367] Step 1: Synthesis of N-(4-methyl-3-(2-((3-methylisoxazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1368] To a solution of 3-methylisoxazol-5-amine (133 mg, 1.36 mmol) in DMF (6 mL) was added NaH (109 mg, 2.72 mmol). The reaction mixture was stirred at room temperature under N ₂ for 1 hour. Then in DMF (12 mL) N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3 A solution of -d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (700 mg crude, 1.36 mmol) was added dropwise to the reaction solution. The resulting solution was stirred at room temperature under N ₂ for 1 hour and quenched with saturated NH ₄ Cl (10 mL) and water (50 mL). The reaction mixture was extracted with EA (30 mL x 2). The organic phase was concentrated in vacuo. The crude product was purified by preparative-HPLC (0.1%/TFA/CH ₃ CN/H ₂ O) to obtain N-(4-methyl-3-(2-((3-methylisoxazole) -5-yl) amino) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-6-yl) phenyl) -4- (tri Fluoromethyl)picolinesulfonamide TFA salt (6.5 mg, 0.7% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.22 (s, 1H), 10.96 (s, 1H), 10.22 (s, 1H), 9.18 (s, 1H), 9.06 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.12 (dd, J = 5.0, 1.2 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.93 (dd, J = 8.0 , 2.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 6.45 (s, 1H), 4.80 (t, J = 9.6 Hz, 2H), 4.14 (t, J = 10.4 Hz, 2H), 2.27 (s, 3H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 547.2.

Example 247: N-(4-methyl-3-(2-((5-methyl-1,3,4-thiadiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 247) manufacturing

[1369] Step 1: Synthesis of N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-5-methyl-1,3,4-thiadiazol-2-amine

[1370] To a solution of 5-methyl-1,3,4-thiadiazol-2-amine (111 mg, 0.96 mmol) in DMF (4 mL) was added NaH (38 mg, 0.96 mmol). The reaction mixture was stirred at room temperature under N2 for 0.5 hour. A solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (150 mg, 0.48 mmol) in DMF (18 mL) was then added dropwise to the reaction solution. The resulting solution was stirred at room temperature under N2 for 1 hour. The solution was quenched with saturated NH4Cl. Water was added and the reaction mixture was extracted with EA. The pooled extracts were washed with brine. Concentration and purification by flash chromatography gave N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-5-methyl-1,3,4-thiadiazol-2-amine (24 mg, 14% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 366.0

[1371] Step 2: Synthesis of N-(4-methyl-3-(2-((5-methyl-1,3,4-thiadiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1372] N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-5-methyl-1,3,4-thiadiazol-2-amine (24 mg, 0.066 mmol) in dioxane (6 mL) and water (2 mL), N-(4-methyl-3-(4,4,5,5-tetramethyl-1 A mixture of ,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (35 mg, 0.0858 mmol), Cs2CO3 (64 mg, 0.198 mmol) and Pd(dppf)Cl2 (10 mg, 0.0132 mmol) was stirred at 100° C. under N2 for 4 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (DCM/MeOH =10/1) to give the crude product which was purified by preparative-HPLC (0.1%/HCl/CH3CN/H2O) to N-(4-methyl-3-(2-((5-methyl-1,3,4-thiadiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyridonium. Midin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide was obtained.

[1373] (2.3 mg, 6% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.95 (s, 1H), 10.26 (s, 1H), 9.21 (s, 1H), 9.05 (d, J = 4.4 Hz, 1H), 8.33 (s, 1H), 8.32 (s, 1H), 8.11 (d, J = 4.4 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 8.4, 2.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.84-4.79 (m, 2H), 4.17-4.11 (m, 2H), 2.68 (s, 3H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 564.1.

Example 248: N-(3-(2-((1,3,4-thiadiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 248) manufacturing

[1374] Step 1: Synthesis of N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-1,3,4-thiadiazol-2-amine

[1375] To a solution of 1,3,4-thiadiazol-2-amine (162 mg, 1.6 mmol) in DMF (4 mL) was added NaH (64 mg, 1.6 mmol). The reaction mixture was stirred at room temperature under N ₂ for 0.5 h. A solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (250 mg, 0.80 mmol) in DMF (24 mL) was then added dropwise to the above reaction solution. The resulting solution was stirred at room temperature under N ₂ for 1 hour. The solution was quenched with saturated NH4Cl. Water was added and the reaction mixture was extracted with EA. The pooled extracts were washed with brine. Purification by flash chromatography after concentration gave N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-1,3,4-thiadiazol-2-amine (33 mg, 14% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 352.0

[1376] Step 2: Synthesis of N-(3-(2-((1,3,4-thiadiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide hydrochloride

[1377] N-(6-Bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-1,3,4-thiadiazol-2-amine (33 mg, 0.09 mmol) in dioxane (6 mL) and water (2 mL), N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2- A mixture of dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (47 mg, 0.117 mmol), Cs2CO3 (87 mg, 0.27 mmol) and Pd(dppf)Cl2 (13 mg, 0.018 mmol) was stirred at 100° C. under N2 for 4 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography to give the crude product which was purified by preparative-HPLC (0.1%/HCl/CH3CN/H2O) to N-(3-(2-((1,3,4-thiadiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoro Romethyl)picolinesulfonamide hydrochloride (6.4 mg, 12% yield) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 10.32 (s, 1H), 9.30 (s, 1H), 9.24 (s, 1H), 9.05 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 8.33 (s, 1H), 8.11 (d, J = 4.4 Hz, 1H), 8.06 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 4.83 (t, J = 10.0 Hz, 2H), 4.15 (t, J = 10.0 Hz, 2H), 2. 22 (s, 3H). LCMS (M+H+) m/z: 550.1.

Example 249: N-(3-(2-((1,2,4-thiadiazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 249) manufacturing

[1378] Step 1: Synthesis of N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-1,2,4-thiadiazol-5-amine

[1379] To a solution of 1,2,4-thiadiazol-2-amine (65 mg, 0.64 mmol) in DMF (2 mL) was added NaH (26 mg, 0.64 mmol). The reaction mixture was stirred at room temperature under N2 for 0.5 hour. A solution of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (100 mg, 0.32 mmol) in DMF (12 mL) was then added dropwise to the above reaction solution. The resulting solution was stirred at room temperature under N2 for 1 hour. The solution was quenched with saturated NH4Cl. Water was added and the reaction mixture was extracted with EA. The pooled extracts were washed with brine. Concentration and purification by flash chromatography gave N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-1,2,4-thiadiazol-5-amine (30 mg, 27% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 351.9

[1380] Step 2: Synthesis of N-(3-(2-((1,2,4-thiadiazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[1381] N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-1,2,4-thiadiazol-5-amine (30 mg, 0.086 mmol), N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2) in dioxane (6 mL) and water (2 mL) A mixture of -dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (52 mg, 0.129 mmol), Cs2CO3 (84 mg, 0.258 mmol) and Pd(dppf)Cl2 (13 mg, 0.0172 mmol) was stirred at 100° C. under N2 for 4 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by column DCM/MeOH =10/1 to give the crude product which was purified by preparative-HPLC (0.1%/HCl/CH3CN/H2O) to N-(3-(2-((1,2,4-thiadiazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl )-4-(trifluoromethyl)picolinesulfonamide (13 mg, 27% yield) was obtained as a yellow solid.

^{[1382] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 13.52 (br, 1H), 10.96 (s, 1H), 10.41 (s, 1H), 9.31 (s, 1H), 9.06 (d, J = 5.2 Hz, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 8.12 (dd, J = 5.2, 1.2 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.93 (dd, J = 8.4, 2.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 4.93-4.90 (m, 2H), 4.21-4.16 (m, 2H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 550.2.

Example 250: N-(3-(2-((1,2,3-thiadiazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 250) manufacturing

[1383] Step 1: Synthesis of N-(3-(2-((1,2,3-thiadiazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide hydrochloride

[1384] To a solution of 1,2,3-thiadiazol-5-amine (47 mg, 0.465 mmol) in DMF (4 mL) was added NaH (37 mg, 0.93 mmol, 60% wt in mineral oil). The reaction mixture was stirred at room temperature under N ₂ for 1 hour. A solution of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (160 mg, 0.31 mmol) in DMF (6 mL) was then added dropwise to the reaction solution. The reaction mixture was stirred at room temperature under N ₂ for 1 hour. The resulting solution was directly purified by flash chromatography to obtain the crude product. The crude product was purified by preparative-HPLC (0.1%/HCl/CHCN/H2O) to N-(3-(2-((1,2,3-thiadiazol-5-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinsulfonamide (5.1 mg , 3% yield) as a yellow solid.

[1385] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.95 (s, 1H), 10.51 (s, 1H), 9.16 (s, 1H), 9.05 (d, J = 5.2 Hz, 1H), 8.34 (d, J = 5.6 Hz, 2H), 8.12 (dd, J = 5.2, 1.2 Hz , 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 8.4, 2.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.50 (t, J = 10.0 Hz, 2H), 4.07 (t, J = 10.0 Hz, 2H), 2.21 (s, 3H). LCMS (M+H ⁺ ) m/z: 550.2.

Example 251: N-(3-(2-((1,3,4-oxadiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 251) manufacturing

[1386] Step 1: Synthesis of N-(3-(2-((1,3,4-oxadiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide 2,2,2-trifluoroacetate

[1387] To a solution of 1,3,4-oxadiazol-2-amine (45 mg, 0.528 mmol) in DMF (3 mL) was added NaH (21 mg, 0.528 mmol). The reaction mixture was stirred at room temperature under N2 for 1 hour. A solution of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (90 mg, 0.176 mmol) in DMF (8 mL) was then added dropwise to the reaction solution. The resulting solution was stirred at room temperature under N ₂ for 1 hour and quenched with saturated NH ₄ Cl (10 mL) and water (60 mL). The reaction mixture was extracted with EA (40 mL x 3). The organic phase was concentrated and the crude product was purified by prep-HPLC (0.1%/TFA/CH ₃ CN/H ₂ O) to yield N-(3-(2-((1,3,4-oxadiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)p Cholinesulfonamide 2,2,2-trifluoroacetate (15 mg, 13% yield) was obtained as a yellow solid.

[1388] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.19 (br, 1H), 10.95 (s, 1H), 10.27 (br s, 1H), 9.18 (s, 1H), 9.11 (s, 1H), 9.06 (d, J = 4.8 Hz, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.12 (dd, J = 5.2, 1.2 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 8.4, 2.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 4.68 (t, J = 10.0 Hz, 2H), 4.09 (t, J = 10.0 Hz, 2H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 534.1.

Example 252: N-(4-methyl-3-(2-((5-methyl-1,3,4-oxadiazol-2-yl)amino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 252) manufacturing

[1389] Step 1: Synthesis of N-(4-methyl-3-(2-((5-methyl-1,3,4-oxadiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide formate

[1390] To a solution of 5-methyl-1,3,4-oxadiazol-2-amine (52 mg, 0.528 mmol) in DMF (3 mL) was added NaH (21 mg, 0.528 mmol). The reaction mixture was stirred at room temperature under N2 for 1 hour. A solution of N-(4-methyl-3-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (90 mg, 0.176 mmol) in DMF (8 mL) was then added dropwise to the reaction solution. The resulting solution was stirred at room temperature under N2 for 1 hour and quenched with saturated NH4Cl (10 mL) and water (60 mL). The reaction mixture was extracted with EA (40 mL x 3). The organic phase was concentrated and the crude product was purified by preparative-HPLC (0.1%/FA/CH3CN/H2O) to obtain N-(4-methyl-3-(2-((5-methyl-1,3,4-oxadiazol-2-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)p Cholinesulfonamide formate (7.5 mg, 7% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (s, 1H), 9.04 (d, J = 4.8 Hz, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.10 (d, J = 4.8 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.27-7.25 (m, 2H), 4.09-4.05 (m, 2H), 3.98-3.94 (m, 2H), 2.47 (s, 3H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 548.2.

Example 253 and 254: N-(3-(2-((1H-1,2,4-triazol-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (Compound 253) and N-(3-(2-(3-amino- 4H-1,2,4-triazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 254) manufacturing

[1391] Prepared similarly to Example 252 using 1H-1,2,4-triazol-3-amine as starting material. Two isomers were obtained, yielding compound 253 (4.4 mg, 4.8% yield) and compound 254 (2.1 mg, 2.3% yield) as yellow solids. LCMS (M+H+) m/z: 530.3.

[1392] 화합물 253 ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.96 (s, 1H), 10.66 (s, 1H), 9.39 (s, 1H), 9.05 (d, J = 5.2 Hz, 1H), 8.49 (s, 1H), 8.33 (s, 1H), 8.11 (dd, J = 5.2, 1.2 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 8.04 (br s, 1H), 7.93 (dd, J = 8.4, 2.4 Hz, 1H), 7.81 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 4.81 (t, J = 10.0 Hz, 2H), 4.15 (t, J = 10.0 Hz, 2H), 2.24 (s, 3H). LCMS (M+H ⁺ ) m/z: 533.3.

[1393] 화합물 254 ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.96 (s, 1H), 10.56 (s, 1H), 9.33 (s, 1H), 9.26 (s, 1H), 9.05 (d, J = 4.8 Hz, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 8.12-8.07 (m, 2H), 7.92 (dd, J = 8.4, 2.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 6.29 (br, 1H), 4.75 (t, J = 10.0 Hz, 2H), 4.15 (t, J = 10.0 Hz, 2H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 533.3.

Example 255: N-(4-methyl-3-(2-(thiazol-2-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 255) manufacturing

[1394] Step 1: Synthesis of N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)thiazol-2-amine

[1395] To a solution of thiazol-2-amine (95.8 mg, 0.96 mmol) in THF (1 mL) was added NaH (46 mg, 1.92 mmol) at 0 ° C and the mixture was stirred at 0 ° C for 1 hour, then 6-bromo-2- (methylsulfinyl) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine (2 00 mg, 0.64 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 2 hours. H ₂ O (30 mL) was added and the reaction mixture was extracted with DCM (30 mL x 3). The combined organic phases were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)thiazol-2-amine (70 mg, 31% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 349.0 and 351.0.

[1396] Step 2: Synthesis of N-(4-methyl-3-(2-(thiazol-2-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[ ₁₃₉₇ ] N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (58.2 mg, 0.14 mmol), Pd(dppf)Cl ₂ (10 mg, 0.014 mmol), Cs ₂ CO ₃ (137 mg, 0.42 mmol) were added, the mixture was degassed 3 times, charged with N ₂ and stirred at 110 °C for 3 h. The reaction mixture was concentrated in vacuo and purified by column chromatography (DCM/ MeOH=10/1) to give the crude product which was purified by preparative-HPLC (0.1% HCOOH) to obtain N-(4-methyl-3-(2-(thiazol-2-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl) Acquired picolinesulfonamide (3.8 mg, 3.5% yield) as a yellow solid.

^{[1398] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 11.81 (s, 1H), 10.78 (s, 1H), 9.04 (d, J = 4.8 Hz, 1H), 8.47 (s, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 8.10 (d, J = 4.8 Hz, 1H), 7.87 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.28-7.25 (m, 2H), 7.18 (d, J = 3.6 Hz, 1H), 4.24 (t, J = 9.2 Hz, 2H), 4.02 (t, J = 9.2 Hz, 2H), 2.24 (s, 3H). LCMS (M+H ⁺ ) m/z: 549.2.

Example 256: N-(4-methyl-3-(2-(thiazol-5-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 256) manufacturing

[0001] Step 1: Synthesis of N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)thiazol-5-amine

[0002] To a solution of thiazol-5-amine hydrochloride (130 mg, 0.96 mmol) in DMF (2 mL) was added NaH (77 mg, 1.92 mmol) at 0 °C and the mixture was stirred at 0 °C for 1 hour, then 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine ( 200 mg, 0.64 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 2 hours. H ₂ O (30 mL) was added and the reaction mixture was extracted with DCM (30 mL x 3). The combined organic phases were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product which was purified by column chromatography (DCM/ MeOH=10/1) to obtain N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)thiazol-5-amine (70 mg, 31% yield) was obtained as a brown solid. LCMS (M+H ⁺ ) m/z: 349.0 and 351.0.

[0003] Step 2: Synthesis of N-(4-methyl-3-(2-(thiazol-5-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[0004] N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (70 mg, 0.17 mmol), Pd(dppf)Cl ₂ (10 mg, 0.014 mmol), Cs ₂ CO ₃ (137 mg, 0.42 mmol) were added and _the mixture was degassed 3 times, then charged with N ₂ and stirred at 110 °C for 5 h. The reaction mixture was concentrated in vacuo and purified by column chromatography (DCM/MeOH=10/1) and by preparative-HPLC (0.1% HCOOH) to obtain N-(4-methyl-3-(2-(thiazol-5-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinsulfonamide (22. 4 mg, 28.5% yield) as a yellow solid.

^{[0005] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 11.11 (br s, 1H), 10.77 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.53 (s, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 8. 17 (s, 1H), 8.10–8.08 (m, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.78 (dd, J =8.4, 2.0 Hz, 1H), 7.63 (s, 1H), 7.26–7.24 (m, 2H), 4.20–4.17 (m, 2H), 4.00 (t, J = 8.8 Hz, 2H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 549.3.

Example 257: N-(3-(2-(isoxazol-5-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 257) manufacturing

[1404] Step 1: Synthesis of N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)isoxazol-5-amine

[1405] To a mixture of isoxazol-5-amine (150 mg, 1.79 mmol) in dry THF, NaH (71 mg, 1.79 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature for 1.0 h under N2. 6-Bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (280 mg, 0.89 mmol) was then added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with cold water (50 mL) and extracted with DCM (50 mL x3). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica column chromatography (DCM:MeOH =15:1) and then triturated with PE/EA (1:1, 2.0 mL) to give N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)isoxazol-5-amine (116 mg, 38.9% yield) as a yellow solid. LCMS (M+H+) m/z: 333.1 and 335.1.

[1406] Step 2: Synthesis of N-(3-(2-(isoxazol-5-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide

[1407] 디옥산 (10.0 mL) 및 H ₂ O (1.1 mL) 중 6-브로모-N-(옥세탄-3-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (100 mg, 0.3 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (146 mg, 0.36 mmol), Cs ₂ CO ₃ (196 mg, 0.6 mmol) 및 [1,1'-비스(디페닐포스피노)페로센]디클로로팔라듐(II) (22 mg, 0.03 mmol)의 혼합물을 80℃에서 16 시간 동안 N ₂ 하에 교반하였다. The reaction mixture was filtered and concentrated. The residue was purified by preparative-HPLC (0.1%FA) to afford N-(3-(2-(isoxazol-5-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (5.1 mg, 3.2% yield) as a yellow solid. 1H NMR (400 MHz, CD ₃ OD): δ 9.12 (s, 1H), 8.97 (d, J = 4.8 Hz, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 7.95-7.94 (m, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 6.62 (s, 1H), 4.85–4.80 (m, 2H), 4.23 (t, J = 10.0 Hz, 2H), 2.30 (s, 3H). LCMS (M+H ⁺ ) m/z: 533.2.

Example 258: N-(3-(2-(isoxazol-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 258) manufacturing

[1408] Step 1: Synthesis of N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)isoxazol-3-amine

[1409] A solution of isoxazol-3-amine (134 mg, 1.6 mmol) and 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (250 mg, 0.80 mmol) in THF:TFA (10:1) (2 mL) was stirred at 70°C for 16 hours. The resulting mixture was concentrated, diluted with saturated NaHCO ₃ (30 mL), then extracted with DCM (50 mL x 3). The combined organic phases were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product which was purified by column chromatography (DCM/MeOH=10/1) to obtain N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)isoxazol-3-amine (130 mg, 4 8.9% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 333.1 and 335.1.

[1410] Step 2: Synthesis of N-(4-methyl-3-(2-(thiazol-2-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1411] N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (61 mg, 0.15 mmol), Pd(dppf)Cl ₂ (12 mg, 0.015 mmol), Cs ₂ CO ₃ (147 mg, 0.45 mmol) were added. The mixture was degassed 3 times, charged with N ₂ , and stirred at 110° C. for 3 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography (DCM/MeOH=10/1) to give the crude product which was purified by preparative-HPLC (0.1% HCOOH) to obtain N-(4-methyl-3-(2-(thiazol-2-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl) Acquired picolinesulfonamide (3.6 mg, 3.2% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.77 (s, 1H), 10.65 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.77 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 8.10-8.08 (m, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.80-7.77 (m, 1H), 7.26-7.24 (m, 2H), 7.19 (d, J = 1.2 Hz, 1H), 4.12 (t, J = 9.2 Hz, 2H), 3.97 (t, J = 9.2 Hz, 2H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 533.3.

Example 259: N-(4-methyl-3-(2-(oxazol-2-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3- d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 259) manufacturing

[1412] Step 1: Synthesis of N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)oxazol-2-amine

[1413] A mixture of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (150 mg, 0.48 mmol) and oxazol-2-amine (80 mg, 0.96 mmol) in DMSO (5 mL) was stirred at 120°C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mLx3), then dried over Na2SO4 and filtered. The combined organic layers were concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=15/1) to give the crude product which was purified by preparative-HPLC (0.1% NH ₃ -H ₂ O) to obtain N-(6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)oxazol-2-amine (40 mg, 25% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 333.0 and 335.0.

[1414] Step 2: Synthesis of N-(4-methyl-3-(2-(oxazol-2-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1415] 디옥산 (5 mL) 및 물 (0.5 mL) 중 N-(6-브로모-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-일)옥사졸-2-아민 (40 mg, 0.12 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란 -2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (48 mg, 0.28 mmol), Cs ₂ CO ₃ (118 mg, 0.36 mmol) 및 Pd(dppf)Cl ₂ (8 mg, 0.01 mmol)의 혼합물을 탈기하고, N ₂ 로 3회 충전하고 80℃에서 16 시간 교반하였다. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=10/1) to give the crude product which was purified by preparative-HPLC (0.1% FA) to N-(4-methyl-3-(2-(oxazol-2-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoro Methyl)picolinesulfonamide (3.7 mg, 5.8 % yield) was obtained as a yellow solid.

^{[1416] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 10.79 (s, 1H), 10.28 (s, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 8.09 (d, J = 4.4 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.34 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.61 (s, 1H), 4.12 (t, J = 8.4 Hz, 2H), 4.03 (t, J = 8.4 Hz, 2H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 533.2.

Example 260: N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide (compound 260) manufacturing

[1417] Step 1: Synthesis of methyl 4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzoate

[1418] 6-Bromo-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (400 mg, 1.16 mmol) in dioxane/H ₂ O (20 mL/2 mL), methyl 4-methyl-3-(4,4,5,5-tetramethyl- To a mixture of 1,3,2-dioxaborolan-2-yl)benzoate (319 mg, 1.16 mmol) was added Pd(dppf)Cl ₂ (85 mg, 0.116 mmol), Cs ₂ CO ₃ (1.13 g, 3.47 mmol). The mixture was stirred at 105° C. for 5 h under N ₂ . The reaction mixture was purified by column chromatography on silica gel (DCM/MeOH=15/1) in vacuum concentration to give methyl 4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzoate (350 mg, 73.1% yield) as a white solid did LCMS (M+H) ⁺ m/z: 416.1.

[1419] Step 2: Synthesis of N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide formic acid salt

[1420] Methyl 4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzoate (90 mg, 0.217 mmol) in dry toluene (10 mL), 5-chloro-4-(trifluoromethyl)pyridine- To a mixture of 2-amine (80 mg, 0.325 mmol) was added Al(Me) ₃ (0.33 mL, 2M, 0.65 mmol) at room temperature under N ₂ . The mixture was stirred at 115° C. for 16 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=10/1) to give the crude product which was purified by preparative-HPLC (0.1% NH ₃ -H ₂ O) to N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[ Obtained 1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide formic acid salt (25.0 mg, 18.4% yield) as a yellow solid.

^{[1421] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 11.40 (s, 1H), 9.80-9.68 (m, 1H), 8.75 (s, 1H), 8.68 (s, 1H), 8.20 (s, 1H), 7.96-7.93 (m, 3H), 7.56 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H), 4.24-4.08 (m, 2H), 3.97 (t, J = 9.2 Hz, 2H), 3.83 (s, 3H), 2.33 (s, 3H). LCMS (M+H ⁺ ) m/z: 580.3.

Example 261: N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)isonicotinesulfonamide (compound 261) manufacturing

[1422] The preparation of 6-(5-amino-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 196.

[1423] Step 1: Synthesis of N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)isonicotinsulfonamide formate

[1424] HATU (92 mg, 0.24 mmol) was added to 6-(5-amino-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.16 mmol), 2-(trifluoromethyl) in DMF (1 mL) To a mixture of sonicotinic acid (37 mg, 0.19 mmol) and DIEA (62 mg, 0.48 mmol) was added. The mixture was stirred at room temperature for 2 hours, diluted with water (50 mL), and filtered. The resulting solid was dried and purified by column chromatography on silica gel (DCM:MeOH=10:1) to give the crude product which was further purified by preparative-HPLC (0.1% HCOOH) to N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6- Obtained yl)phenyl)-2-(trifluoromethyl)isonicotinesulfonamide formate (50 mg, 56.9% yield) as a yellow solid.

^{[1425] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 10.67 (s, 1H), 9.83 (br, 1H), 8.99 (d, J = 5.2 Hz, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.20 (d, J = 4.8 Hz, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.70-7.67 (m, 2H), 7.56 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 4.24-4.20 (m, 2H), 3.97 (t, J = 9.2 Hz, 2H), 3.58 (s, 3H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 546.6.

Example 262: 3-chloro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 262) manufacturing

[1426] Step 1: Synthesis of 3-chloro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1427] A mixture of dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.16 mmol), 3-chloro-4-(trifluoromethyl)picolinic acid (36 mg, 0.16 mmol), HATU (92 mg, 0.24 mmol) and DIEA (62 mg, 0.48 mmol) in dry DMF (3 mL) It was stirred for 2 hours at room temperature. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with DCM (30 mLx3). The combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=10/1) to give the crude product which was triturated with MeOH (1 mL) to obtain 3-chloro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2, Obtained 3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (27.4 mg, 29.3 % yield) as a yellow solid.

[1428] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (s, 1H), 8.78-9.69 (m, 1H), 8.88 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 8.05 (d, J = 4.8 Hz, 1H), 7.93 (s, 1H), 7.65 (s, 1H), 7.55 (dd, J = 8.4, 2.4 Hz, 2H), 7.28-7.21 (m, 2H), 4.21-4.20 (m, 2H), 3.97 (t, J = 8.2 Hz, 2H), 3.82 (s, 3H), 2.21 (s, 3H). LCMS (M+H ⁺ ) m/z: 580.6.

Example 263: 5-chloro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 263) manufacturing

[1429] Step 1: Synthesis of 5-chloro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1430] 5-chloro-4- (trifluoromethyl) picolinic acid (36 g, 0 .16 mmol), HATU (92 mg, 0.24 mmol), DIPEA (62 mg, 0.48 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture and the obtained solid was filtered and purified by column chromatography (DCM:MeOH=15:1) to obtain 5-chloro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl) ) Ficolinsulfonamide (34.5 mg, 36.9% yield) was obtained as a yellow solid.

[1431] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.79 (s, 1H), 9.87 (s, 1H), 9.09 (s, 1H), 8.37 (s, 2H), 7.93 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.78 ( dd, J = 8.4, 2.0 Hz, 1H), 7.57 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.25–4.21 (m, 2H), 3.98 (t, J = 8.4 Hz, 2H), 3.83 (s, 3H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 580.2.

Example 264: 4-chloro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzsulfonamide (compound 264) manufacturing

[1432] Step 1: Synthesis of 4-chloro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzsulfonamide formate

[1433] HATU (92 mg, 0.24 mmol) was added to 6-(5-amino-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.16 mmol), 4-chloro-3-(trifluoro) in DMF (1 mL) Romethyl)benzoic acid (43 mg, 0.19 mmol) and DIEA (62 mg, 0.48 mmol) were added to a mixture. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL). The obtained spheres were filtered, dried and purified by column chromatography on silica gel (DCM: MeOH=10:1) and preparative-HPLC (0.1% HCOOH) to obtain 4-chloro-N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl) Obtained -3-(trifluoromethyl)benzsulfonamide formate (45 mg, 48.2% yield) as a yellow solid.

[1434] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.48 (s, 1H), 9.80 (br, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.19 (s, 1H), 7.93-7.91 (m, 2H), 7.68-7.65 (m, 2H), 7.56-7.54 (m, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 4.20-4.16 (m, 2H), 3.97 (t, J = 9.2 Hz, 2H), 3.82 (s, 3H), 2.22 (s, 3H). LCMS (M+H ⁺ ) m/z: 579.2.

Example 265 N-(4- methyl -3-(2-((1- methyl -1H- pyrazole -4-yl) amino) -9,10- dihydro -8H-pyrido [1,6- a:2 ,3-d'] dipyrimidine -6-yl) phenyl) -4- ( trifluoromethyl ) picolinesulfonamide formate (compound 265) manufacturing

[1435] Step 1: Synthesis of 6-(2,4-difluorophenoxy)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[1436] To a mixture of 6-bromo-2-(methylthio)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (300 mg, 0.96 mmol) in DCM (10 mL) was added m-CPBA (390 mg, 1.93 mmol) at 0°C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was concentrated to give the crude product, which was purified by silica column chromatography (DCM: MeOH = 10: 1) to give 6-(2,4-difluorophenoxy)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (300 mg, crude) as a brown solid. LCMS (M+H+) m/z: 327.0 and 329.0

[1437] Step 2: Synthesis of 6-bromo-N-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine

[1438] To a solution of 6-bromo-2-(methylsulfinyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine (300 mg, 0.92 mmol) in DMSO (10 mL) was added 1-methyl-1H-pyrazol-4-amine hydrochloride (122 mg, 0.92 mmol). The reaction mixture was stirred at 120°C for 16 hours. The mixture was purified by preparative-HPLC (0.1% ammonia) to give 6-bromo-N-(1-methyl-1H-pyrazol-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine (90 mg, 27% yield) as a brown solid. LCMS (M+H+) m/z: 359.9 and 361.9

[1439] Step 3: Synthesis of N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide formate

[1440] 디옥산/H ₂ O (10:1) (2 mL) 중 6-브로모-N-(1-메틸-1H-피라졸-4-일)-9,10-디히드로-8H-피리도 [1,6-a:2,3-d']디피리미딘-2-아민 (70 mg, 1.17 mmol), N-(4-메틸-3-(4,4,5,5-테트라메틸-1,3,2- 디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (95 mg, 0.23 mmol), Cs ₂ CO ₃ (190 mg, 0.58 mmol) 및 Pd(dppf)Cl ₂ (87.8 mg, 0.12 mmol)의 혼합물을 N ₂ 하에 110℃에서 5시간 교반하였다. The reaction mixture was concentrated and purified by silica column (DCM: MeOH=10:1) to give the crude product which was further purified by preparative-HPLC (0.1% FA) to N-(4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)phenyl)-4-(tri) Fluoromethyl)picolinesulfonamide formate (39.7 mg, 36.5% yield) was obtained as a yellow solid.

^{[1441] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 10.75 (s, 1H), 9.93 (s, 1H), 9.03 (d, J = 4.8 Hz, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.24 (s, 1H), 8.09 (d, J = 4.8 Hz, 1H), 7.89 (s, 1H), 7.78-7.76 (m, 2H), 7.60 (s, 1H), 7.23 (d, J = 7.6 Hz, 1H), 4.23 (t, J = 7.6 Hz, 2H), 3.84 (s, 3H), 3.42-3.36 (m, 2H), 2.32 (s, 3H), 1.99-1.97 (m, 2H). LCMS (M+H+) m/z: 560.3.

Example 266 3-(4-fluorophenyl)-1-isopropyl-N-(4-methyl-3-(2-((6-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxsulfone Preparation of Amide (Compound 266)

[1442] The preparation of 6-bromo-N-(6-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 208.

[1443] Step 1: Synthesis of 6-(5-amino-2-methylphenyl)-N-(6-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1444] 디옥산 (5 mL) 및 물 (0.5 mL) 중 6-브로모-N-(6-메틸피리딘-3-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (40 mg, 0.112 mmol), 4-메틸-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)아닐린 (55 mg, 0.134 mmol), Cs ₂ CO ₃ (110 mg, 0.337 mmol) 및 Pd(dppf)Cl ₂ (8 mg, 0.01 mmol)의 혼합물을 탈기하고 N2로 3회 충전한 다음 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=10/1) to give 6-(5-amino-2-methylphenyl)-N-(6-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (30 mg, 70% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 384.3.

[1445] Step 2: 3-(4-fluorophenyl)-1-isopropyl-N-(4-methyl-3-(2-((6-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- Synthesis of carboxsulfonamide formic acid

[1446] 6-(5-amino-2-methylphenyl)-N-(6-methylpyridin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (20 mg, 0.052 mmol), 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1, in DMF (3.0 mL) To a solution of 2,3,4-tetrahydropyrimidine-5-carboxylic acid (17 mg, 0.057 mmol) and HATU (40 mg, 0.104 mmol) was added DIEA (14 mg, 0.104 mmol). The resulting mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was quenched with water (20 mL) and extracted with DCM (20 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO4, filtered and concentrated to give the crude product which was purified by preparative-HPLC (0.1% FA) to obtain 3-(4-fluorophenyl)-1-isopropyl-N-(4-methyl-3-(2-((6-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido Obtained [2,3-d]pyrimidin-6-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxsulfonamide formic acid (9.3 mg, 25.3% yield) as a yellow solid.

^{[1447] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 10.82 (s, 1H), 9.89 (s, 1H), 8.83 (s, 1H), 8.62 (s, 1H), 8.36 (s, 1H) ), 8.15 (s, 1H), 8.12–8.10 (m, 1H), 7.57–7.55 (m, 2H), 7.43–7.40 (m, 2H), 7.34 (t, J = 8.8 Hz, 2H), 7.22– 7.17 (m, 3H), 4.80-4.73 (m, 1H), 4.12 (t, J = 9.6 Hz, 2H), 3.95 (t, J = 9.6 Hz, 2H), 2.41 (s, 3H), 2.20 (s , 3H), 1.40 (d, J = 6.8 Hz, 6H). LCMS (M+H ⁺ ) m/z: 658.3.

Example 267: N-(2-fluoro-4-methyl-5-(2-((6-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 267) manufacturing

[1448] Step 1: Synthesis of N-(2-fluoro-4-methyl-5-(2-((6-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1449] 디옥산/H ₂ O (10 mL/1 mL) 중 6-브로모-N-(6-메틸피리딘-3-일)-8,9-디히드로이미다조[1',2':1,6] 피리도[2,3-d]피리미딘-2-아민 (110 mg, 0.31 mmol)의 용액에 N-(2-플루오로-4-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-4-(트리플루오로메틸)피콜린설폰아미드 (156 mg, 0.37 mmol), Pd(dppf)Cl ₂ (23 mg, 0.031 mmol), Cs ₂ CO ₃ (301 mg, 0.92 mmol)르르 첨가하였다. The mixture was stirred at 120° C. for 2 h under N ₂ and concentrated. The residue was purified by column chromatography (EA:MeOH=10:1) to obtain N-(2-fluoro-4-methyl-5-(2-((6-methylpyridin-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (30 mg, 20.5% yield) was obtained as a yellow solid.

[1450] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.49 (s, 1H), 10.02 (br s, 1H), 9.06 (d, J = 5.2 Hz, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.50 (s, 1H), 8.33 (s, 1H), 8.14-8.10 (m, 2H), 7.88 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.32 (d, J = 11.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.24-4.20 (m, 2H), 4.01-3.96 (m, 2H), 2.42 (s, 3H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 575.2.

Example 268: N-(2-fluoro-4-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 268) manufacturing

[1451] The preparation of 6-(5-amino-4-fluoro-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 201.

[1452] Step 1: Synthesis of N-(2-fluoro-4-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1453] 6-(5-amino-4-fluoro-2-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (150 mg, 0.38 mmol), 4-(trifluoromethyl)picolinic acid (74 mg, 0 .38 mmol), HATU (219 mg, 0.58 mmol) and DIEA (149 mg, 1.15 mmol) were stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% FA) to obtain N-(2-fluoro-4-methyl-5-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (10.3 mg, 4.8 % yield) was obtained as a yellow solid.

^{[1454] 1} H NMR (400 MHz, DMSO-d ₆ ): δ 10.46 (s, 1H), 9.80 (br, 1H), 9.05 (d, J = 4.8 Hz, 1H), 8.33-8.30 (s, 4H), 8.13 (d, J = 4.0 Hz, 1H), 7.92 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.53-7.55 (m, 1H), 7.27 (d, J = 11.6 Hz, 1H), 7.20 (s, 1H), 4.20-4.16 (m, 2H), 3.99-3.94 (m, 2H), 3.82 (s, 3H), 2.25 (s, 3H). ¹⁹ F NMR (400 MHz, DMSO-d ₆ ): δ -126.94 (s, 1F), -63.47 (s, 3F). LCMS (M+H ⁺ ) m/z: 564.1.

Example 269: N-(2-fluoro-4-methyl-5-(2-((1-methyl-1H-pyrazol-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 269) manufacturing

[1455] The preparation of 6-bromo-N-(1-methyl-1H-pyrazol-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 234.

[1456] Step 1: Synthesis of 6-(5-amino-4-fluoro-2-methylphenyl)-N-(1-methyl-1H-pyrazol-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1457] 디옥산 (5.0 mL) 및 H ₂ O (0.5 mL) 중 6-브로모-N-(1-메틸-1H-피라졸-3-일)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d] 피리미딘-2-아민 (180 mg, 0.52 mmol), 2-플루오로-4-메틸-5-(4,4,5,5-테트라메틸- 1,3,2-디옥사보롤란-2-일)아닐린 (144 mg, 0.57 mmol), Cs ₂ CO ₃ (508 mg, 1.56 mmol) 및 [1,1'-비스(디페닐포스피노)페로센]디클로로팔라듐(II) (38 mg, 0.052 mmol)의 혼합물을 100℃에서 16 시간 동안 N ₂ 하에 교반하였다. The reaction mixture was concentrated and purified by column chromatography on silica gel (DCM:MeOH=10:1) to give 6-(5-amino-4-fluoro-2-methylphenyl)-N-(1-methyl-1H-pyrazol-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (100 mg, 49% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 391.0.

[1458] Step 2: Synthesis of N-(2-fluoro-4-methyl-5-(2-((1-methyl-1H-pyrazol-3-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide formic acid salt

[1459] 4- (trifluoromethyl) picolinic acid (40.4 mg, 0.211 mmol) in DMF (7.0 mL), 6- (5-amino-4-fluoro-2-methylphenyl) -N- (1-methyl-1H-pyrazol-3-yl) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (75 mg, 0.192 mmol) and HATU (110 mg, 0.288 mmol) was added DIEA (74 mg, 0.576 mmol). The resulting mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was added slowly to water (40 mL), stirred at room temperature for 30 minutes and filtered. The collected cake was purified by column chromatography on silica gel (DCM:MeOH=10:1, +0.1% NH ₃ -MeOH) to give the crude product which was purified by preparative-HPLC (0.1%TA) to obtain N-(2-fluoro-4-methyl-5-(2-((1-methyl-1H-pyrazol-3-yl)amino)-8,9-dihydroimidazo [1',2':1,6]pyr Obtained do[2,3-d]pyrimidin-6-yl)phenyl)-4-(trifluoromethyl)picolinesulfonamide formic acid salt (30.2 mg, 26% yield) as a yellow solid.

^{[1460] 1} H NMR (400 MHz, CD ₃ OD): δ 9.01 (d, J = 4.8 Hz, 1H), 8.98 (s, 1H), 8.46 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 4.8 Hz, 1H), 7.92 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 11.6 Hz, 1H), 6.76 (br, 1H), 4.86-4.81 (m, 2H), 4.24 (t, J = 10.0 Hz, 2H), 3.88 (s, 3H), 2.30 (s, 3H). LCMS (M+H ⁺ ) m/z: 564.2.

Example 270: 2-fluoro-4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (compound 270) manufacturing

[1461] Step 1: Synthesis of 4-bromo-2-fluoro-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1462] To a solution of 4-bromo-2-fluorobenzoic acid (1.1 g, 5 mmol) in DCM (15 mL) was added SOCl ₂ (2.38 g, 20 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated to obtain a crude solid. The crude solid was dissolved in DCM (20 mL) then 4-(trifluoromethyl)pyridin-2-amine (810 mg, 5 mmol) and TEA (1.01 g, 10 mmol) were added at 0 °C and the reaction mixture was stirred at 25 °C for 16 h. LCMS showed the reaction to be complete. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL*3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated to give a white solid which was purified by chromatography column (PE:EA=4:1) to give compound 1 (620 mg, 34% yield). LCMS (M+H ⁺ ) m/z: 362.8

[1463] Step 2: Synthesis of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1464] To a solution of 4-bromo-2-fluoro-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (620 mg, 1.71 mmol) in dioxane (10 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (434 mg, 1.71 mmol) ), KOAc (335 mg, 3.42 mmol) and Pd(dppf)Cl ₂ (124 mg, 0.17 mmol) were added under nitrogen atmosphere. The mixture was stirred at 100 °C for 2 hours. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by chromatography column (PE:EA=2:1) to obtain 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (33 0 mg, 47% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 411.2

[1465] Step 3: Synthesis of 2-fluoro-4-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1466] 디옥산 (4 mL) 및 H2O (1 mL) 중 2-플루오로-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-N-(4-(트리플루오로메틸)피리딘-2-일)벤즈설폰아미드 (200 mg, 0.48 mmol)의 용액에 6-브로모-2-(메틸티오)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘 (142 mg, 0.48 mmol), K ₂ CO ₃ (132 mg, 0.96 mmol) 및 Pd(dppf)Cl ₂ (37 mg, 0.05 mmol)를 질소 분위기 하에 첨가하였다. The mixture was stirred at 90° C. for 3 h. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by chromatography column (PE:EA=1:2) to obtain 2-fluoro-4-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoro) Romethyl)pyridin-2-yl)benzsulfonamide (90 mg, 38% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 501.2

[1467] Step 4: Synthesis of 2-fluoro-4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1468] To a solution of 2-fluoro-4-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (90 mg, 0.18 mmol) in DCM (5 mL) was m-CPBA (62 mg, 0.36 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. LCMS showed the reaction to be complete. The reaction mixture was concentrated to give a yellow solid. To the crude solid in THF (3 mL) was added methylamine in THF (1 mL, 2 mmol). The mixture was stirred at room temperature for 1 hour. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by prep-HPLC to give 2-fluoro-4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridine-2 -yl)benzsulfonamide (14.4 mg, 17% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.27 (s, 1H), 8.67 (d, J = 5.2 Hz, 1H), 8.53 (s, 1H), 8.37-8.32 (m, 1H), 8.04 (d, J = 12.8 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 6.0 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.70-7.60 (m, 1H), 7.57 (d, J = 5.2 Hz, 1H), 4.12-3.94 (m, 4H), 2.86 (s, 3H). LCMS (M+H ⁺ ) m/z: 484.0.

Example 271: 2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(3-(trifluoromethyl)phenyl)benzsulfonamide (compound 271) manufacturing

[1469] Step 1: Synthesis of 5-bromo-2-fluoro-N-(3-(trifluoromethyl)phenyl)benzsulfonamide

[1470] A mixture of 5-bromo-2-fluorobenzoic acid (0.70 g, 3.2 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.82 g, 4.8 mmol) in DMF (15.0 mL) was stirred at room temperature for 0.5 hour, then 3-(trifluoromethyl)aniline (0.618 g, 3.8 mmol) and N,N-diisopropylethylamine (1.24 g, 9.6 mmol) were added. The obtained mixture was stirred at room temperature for 2.0 hours and then H ₂ O (50 mL) was added. The reaction mixture was extracted with EA (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA = 10/1) to give 5-bromo-2-fluoro-N-(3-(trifluoromethyl)phenyl)benzsulfonamide (980 mg, 85% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 361.9 and 363.9.

[1471] Step 2: Synthesis of 2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -N- (3- (trifluoromethyl) phenyl) benzsulfonamide

[1472] 5-Bromo-2-fluoro-N-(3-(trifluoromethyl)phenyl)benzsulfonamide (1.0 g, 2.70 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.1 g, 8.10 mmol) in dioxane (40.0 mL), Pd( A mixture of dppf)Cl ₂ (0.2 g, 0.27 mmol) and KOAc (0.8 g, 8.10 mmol) was charged to a flask, degassed and then charged with Ar three times and then stirred at 100° C. for 16 hours. The reaction mixture was concentrated. H ₂ O (50 mL) was added and the mixture was extracted with EA (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA=10/1) to give 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(3- (trifluoromethyl) phenyl)benzsulfonamide (550 mg, 50% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 410.0.

[1473] Step 3: Synthesis of 2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(3-(trifluoromethyl)phenyl)benzsulfonamide

[1474] 디옥산 (6.6 mL) 및 H ₂ O (0.66 mL) 중 2-플루오로-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-N-(3-(트리플루오로메틸)페닐)벤즈설폰아미드 (0.6 g, 0.54 mmol), 6-브로모-N-메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (0.1 g, 0.36 mmol)의 혼합물을에 Pd(dppf)Cl ₂ (0.03 g, 0.04 mmol) 및 Cs ₂ CO ₃ (0.35 g, 1.1 mmol)를 첨가하였다. The resulting mixture was degassed, charged with N ₂ three times, and then stirred at 100° C. for 3 hours. The reaction mixture was concentrated. H ₂ O (50 mL) was added and the mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to afford 2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(3-(trifluoromethyl)phenyl)benzsulfonamide (30 mg, 17% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.37 (s, 1H), 10.51 (s, 1H), 8.88 (s, 1H), 8.55 (d, J = 4.8 Hz, 1H), 8.31 (s, 2H), 8.09 (d, J = 8.0 Hz, 1H), 7.90-7.88 (m, 1H), 7.76-7.73 (m, 1H), 7.64-7.55 (m, 2H), 7.49 (d, J = 7.6 Hz, 1H), 4.65-4.52 (m, 2H), 4.08 (t, J = 10.0 Hz, 2H), 2.96 (d, J = 4.4 Hz, 3H). LCMS (M+H ⁺ ) m/z: 483.3.

Example 272 N-(3- chlorophenyl )-2- Fluoro -5-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)benzsulfonamide (compound 272) manufacturing

[1475] Step 1: Synthesis of 5-bromo-2-fluoro-N-(3-(trifluoromethyl)phenyl)benzsulfonamide

[1476] A mixture of 5-bromo-2-fluorobenzoic acid (0.70 g, 3.2 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.82 g, 4.8 mmol) in DMF (15.0 mL) was stirred at room temperature for 0.5 hour, then 3-chloroaniline (0.49 g, 3.8 mmol) and N,N-diisopropylethylamine (1.24 g, 9.6 mmol) were added. The mixture was stirred at room temperature for 2 hours. H ₂ O (50 mL) and extracted with EA (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA=10/1) to give 5-bromo-2-fluoro-N-(3-(trifluoromethyl)phenyl)benzsulfonamide (600 mg, 57% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 329.9.

[1477] Step 2: Synthesis of N-(3-chlorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzsulfonamide

[1478] 5-Bromo-N-(3-chlorophenyl)-2-fluorobenzsulfonamide (0.60 g, 1.8 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.40 g, 5.5 mmol), Pd(dppf)Cl in dioxane (18.0 mL) A mixture of ₂ (0.13 g, 0.18 mmol) and KOAc (0.54 g, 5.5 mmol) was charged to a flask, degassed and charged with Ar three times. The reaction mixture was stirred at 100 °C for 16 hours, then concentrated H ₂ O (50 mL) was added and the mixture was extracted with EA (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA=10/1) to give N-(3-chlorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzsulfonamide (320 mg, 56% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 376.1.

[1479] Step 3: Synthesis of N-(3-chlorophenyl)-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide

[1480] N-(3-chlorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzsulfonamide (0.15 g, 0.39 mmol) in dioxane (10.0 mL) and H ₂ O (1.0 mL), 6-bromo-N-methyl-8,9-dihydroimidazo[1',2': To a mixture of 1,6]pyrido[2,3-d]pyrimidin-2-amine (0.10 g, 0.35 mmol), Pd(dppf)Cl ₂ (0.03 g, 0.04 mmol) and Cs ₂ CO ₃ (0.35 g, 1.1 mmol) were added. The mixture was degassed, charged with N ₂ three times, and stirred at 100° C. for 3 hours. The reaction mixture was concentrated. H ₂ O (50 mL) was added and the mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by trituration to afford N-(3-chlorophenyl)-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide (66 mg, 42% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.64 (s, 1H), 8.30-8.23 (m, 1H), 8.19-8.17 (m, 1H), 8.15-8.12 (m, 1H), 7.92 (s, 1H), 7.63-7.62 (m, 2H), 7.50–7.46 (m, 1H), 7.42–7.36 (m, 2H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H), 4.04–3.96 (s, 4H), 2.84 (s, 3H). LCMS (M+H ⁺ ) m/z: 449.3.

Example 273:4 -(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (compound 273) manufacturing

[1481] Step 1: Synthesis of 4-bromo-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1482] A mixture of 4-bromobenzoic acid (1.0 g, 4.97 mmol), 4-(trifluoromethyl)pyridin-2-amine (886 mg, 5.47 mmol), DIEA (1.9 g, 14.9 mmol) and HATU (2.83 g, 7.45 mmol) in DMF (15.0 mL) was stirred at room temperature for 10 hours. The reaction mixture was diluted with water (150 mL) and extracted with EA (100 mL x 2). The combined organic phases were washed with brine (100 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA=4/1) to give 4-bromo-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (1.05 g, 62% yield) as a pale yellow solid. LCMS (M+H ⁺ ) m/z: 345.0 and 347.0.

[1483] Step 2: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1484] 4-bromo-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (948 mg, 2.75 mmol), bis(pinacolato)diboron (1.39 g, 5.49 mmol), KOAc (808 mg, 8.25 mmol) and Pd(dppf)Cl ₂ (201 mg, 0.2 mmol) in dioxane (25.0 mL) 75 mmol) was degassed, charged with N ₂ three times and stirred at 110° C. for 16 hours. The reaction mixture was concentrated and purified by column chromatography (PE/EA=10/1) to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (900 mg, 83% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 393.2.

[1485] Step 3: Synthesis of 4-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1486] 디옥산 (20.0 mL) 및 물 (5.0 mL) 중 4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-N-(4-(트리플루오로메틸)피리딘-2-일)벤즈설폰아미드(728 mg, 1.86 mmol), 6-브로모-2-(메틸티오)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘 (500 mg, 1.69 mmol), Cs ₂ CO ₃ (1.65 g, 5.07 mmol) 및 Pd(dppf)Cl ₂ (123 mg, 0.17 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전하고 85℃에서 1.5 시간 교반하였다. Responsible mixture and column chromatography (PE/EA = 1/2, +0.1% tea) and 4- (2- (methylthio) -8,9-dihydro already dazo [1 ', 2': 1,6] flute [2,3-d] pyrimidin-6-yl) --n- (trifluoromethyl) Zsulphone amide (793 mg, 88% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 482.9.

[1487] Step 4: Synthesis of 4-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1488] m-CPBA (135 mg, 0.77 mmol) in a solution of 4-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (150 mg, 0.3 mmol) in dry DCM (15 mL) was added at 0 °C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was concentrated in vacuo at room temperature to afford crude 4-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (150 mg, crude) as a yellow solid which was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 499.0.

[1489] Step 5: Synthesis of 4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1490] MeNH ₂ (2 M in THF, 2 M in THF, 0.6 mL, 1.2 mmol) was added. The mixture was stirred at room temperature for 16 hours and concentrated. Water (80 mL) was added. The mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% NH ₃ -H ₂ O) to afford 4-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (46 mg, 32% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.28 (s, 1H), 8.69 (d, J = 5.2 Hz, 1H), 8.57 (s, 1H), 8.33-8.27 (m, 1H), 8.09-8.04 (m, 4H), 7.68 (s, 1H), 7 .55-7.49 (m, 2H), 4.02-4.04 (m, 4H), 2.85 (s, 3H). LCMS (M+H ⁺ ) m/z: 466.3.

Example 274 N-(2- Fluoro -5-( trifluoromethyl )phenyl)-4-(2-( methylamino )-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide (compound 274) manufacturing

[1491] Step 1: Synthesis of 4-bromo-N-(2-fluoro-5-(trifluoromethyl)phenyl)benzsulfonamide

[1492] A mixture of 4-bromobenzoic acid (2.0 g, 9.95 mmol), 2-fluoro-5-(trifluoromethyl)aniline (1.96 g, 10.9 mmol), DIEA (3.8 g, 29.8 mmol) and HATU (5.67 g, 14.9 mmol) in DMF (25.0 mL) was stirred at room temperature for 1.0 hours. The reaction mixture was diluted with water (150 mL) and extracted with EA (100 mL x 2). The combined organic phases were washed with brine (100 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA=4/1) to give 4-bromo-N-(2-fluoro-5-(trifluoromethyl)phenyl)benzsulfonamide (2.79 g, 77% yield) as a pale yellow solid. LCMS (M+H ⁺ ) m/z: 361.8

[1493] Step 2: Synthesis of N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzsulfonamide

[1494] 4-Bromo-N-(2-fluoro-5-(trifluoromethyl)phenyl)benzsulfonamide (2.68 g, 7.4 mmol), bis(pinacolato)diboron (3.7 g, 14.8 mmol), KOAc (2.17 g, 22.2 mmol) and Pd(dppf)Cl ₂ (540 mg, 0.7 mmol) in dioxane (35.0 mL) 4 mmol) was degassed, charged with N ₂ three times, and stirred at 110° C. for 16 hours. The reaction mixture was concentrated and purified by column chromatography (PE/EA=10/1) to give N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzsulfonamide (2.5 g, 83% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 410.2.

[1495] Step 3: Synthesis of N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide

[1496] 디옥산 (20.0 mL) 및 물 (5.0 mL) 중 N-(2-플루오로-5-(트리플루오로메틸)페닐)-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)벤즈설폰아미드 (1.2 g, 1.86 mmol), 6-브로모-2-(메틸티오)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘 (500 mg, 1.69 mmol), Cs ₂ CO ₃ (1.65 g, 5.07 mmol) 및 Pd(dppf)Cl ₂ (123 mg, 0.17 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전하고 85℃에서 1.5 시간 교반하였다. The reaction mixture is concentrated and column chromatography (PE/EA = 1/2, +0.1% TEA), n- (2-fluoro-5- (trifluoromethyl) phenyl) -4- (2- (methylthio) -8,9-dihydro already dazzo [1 ', 2': 1,6] Benz sulfonamide (730 mg, 52% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 500.0.

[1497] Step 4: Synthesis of N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide

[1498] To a solution of N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide (150 mg, 0.3 mmol) in dry DCM (15 mL) was added m-CPBA (156 mg, 0.9 mmol). It was added at 0 °C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was concentrated at room temperature to afford crude N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide (150 mg, crude) as a yellow solid which was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 516.0.

[1499] Step 5: Synthesis of N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide

[1500] MeNH ₂ (2 M in THF, 0 .56 mL, 1.13 mmol) was added. The mixture was stirred at room temperature for 16 hours and concentrated. Water (80 mL) was added and the mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was concentrated by preparative-HPLC (0.1% NH ₃ -H ₂ O) to afford N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide (53.5 mg, 38% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.36 (s, 1H), 8.34-8.28 (m, 1H), 8.12-8.06 (m, 3H), 8.00 (d, J = 8.4 Hz, 2H), 7.68 (s, 2H), 7.60-7.51 (m, 2 H), 4.07–3.98 (m, 4H), 2.86 (s, 3H). LCMS (M+H ⁺ ) m/z: 483.3.

Example 275: N-(2- chlorophenyl )-4-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)benzsulfonamide (compound 275) manufacturing

[1501] Step 1: Synthesis of 4-bromo-N-(2-chlorophenyl)benzsulfonamide

[1502] A mixture of 4-bromobenzoic acid (2.0 g, 9.95 mmol), 2-chloroaniline (1.39 g, 10.9 mmol), DIEA (4.2 g, 32.8 mmol) and HATU (6.2 g, 16.4 mmol) in DMF (25.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (150.0 mL) and extracted with EA (100 mL x 2). The combined organic phases were washed with brine (100 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA=5/1) to give 4-bromo-N-(2-chlorophenyl)benzsulfonamide (2.6 g, 86% yield) as a pale yellow solid. LCMS (M+H ⁺ ) m/z: 310.0 and 312.0.

[1503] Step 2: Synthesis of N-(2-chlorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzsulfonamide

[1504] A mixture of 4-bromo-N-(2-chlorophenyl)benzsulfonamide (2.5 g, 8.06 mmol), bis(pinacolato)diboron (4.09 g, 16.12 mmol), KOAc (2.36 g, 24.18 mmol) and Pd(dppf)Cl ₂ (589 mg, 0.806 mmol) in dioxane (35.0 mL) It was degassed, charged with N ₂ three times, and stirred at 110° C. for 16 hours. The reaction mixture was concentrated and purified by column chromatography (PE/EA=10/1) to give N-(2-chlorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzsulfonamide (2.3 g, 82% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 358.3.

[1505] Step 3: Synthesis of N-(2-chlorophenyl)-4-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide

[1506] N-(2-chlorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- in dioxane (20.0 mL) and water (5.0 mL) 2-yl)benzsulfonamide (663 mg, 1.86 mmol), 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2 A mixture of ,3-d]pyrimidine (500 mg, 1.69 mmol), Cs ₂ CO ₃ (1.65 g, 5.07 mmol) and Pd(dppf)Cl ₂ (123 mg, 0.17 mmol) was degassed with N ₂ three times. It was charged and stirred at 85° C. for 1.5 hours. The reaction mixture was concentrated and purified by column chromatography (PE/EA=1/2, +0.1% TEA) to give N-(2-chlorophenyl)-4-(2-(methylthio)-8,9-dihydro Obtained imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide (612 mg, 73% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 447.9.

[1507] Step 4: Synthesis of N-(2-chlorophenyl)-4-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide

[1508] To a solution of N-(2-chlorophenyl)-4-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide (316 mg, 0.7 mmol) in dry DCM (15 mL) was added m-CPBA (367 mg, 2.12 mmol) at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was concentrated at room temperature to give crude N-(2-chlorophenyl)-4-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide (680 mg, crude) as a yellow solid which was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 464.0.

[1509] Step 5: Synthesis of N-(2-chlorophenyl)-4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide

[1510] To a solution of crude N-(2-chlorophenyl)-4-(2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide (680 mg, 1.46 mmol) in THF (15 mL) MeNH ₂ (2 M in THF, 1.4 mL, 2.85 mmol) ) was added. The mixture was stirred at room temperature for 16 hours and concentrated. Water (80 mL) was added and the mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-HPLC (0.1% NH ₃ -H ₂ O) to afford N-(2-chlorophenyl)-4-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)benzsulfonamide (37.9 mg, 3.1% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.05 (s, 1 H), 8.33-8.26 (m, 1H), 8.06 (d, J = 8.0 Hz, 2H), 8.0 (d, J = 8.8 Hz, 2H), 7.65 (s, 1H), 7.61 (dd, J = 7.6, 1.6 Hz, 1H), 7.57 (dd, J = 8.0, 1.6 Hz, 1H), 7.50 (s, 1H), 7.40 (td, J = 8.0, 1.6 Hz, 1H) 7.30 (td, J = 7.6, 1.6 Hz, 1H), 4.04-4.01 (m, 4H), 2.85 (s, 3H). LCMS (M+H ⁺ ) m/z: 431.3.

Example 276:3 - methyl -4-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (compound 276) manufacturing

[1511] Step 1: Synthesis of 4-bromo-3-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1512] A mixture of 4-(trifluoromethyl)pyridin-2-amine (500 mg, 3.09 mmol), 4-bromo-3-methylbenzoic acid (660 mg, 3.09 mmol), HATU (1.76 g, 4.63 mmol) and DIEA (1.19 g, 9.26 mmol) in DMF (10.0 mL) was stirred at 80 °C for 16 hours. The reaction was cooled to room temperature, diluted with water (50.0 mL) and extracted with EA (80 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over Na ₂ SO ₄ , filtered, concentrated and purified by column chromatography (PE/EA=10/1) to give 4-bromo-3-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (670 mg, 60 % yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 359.0 and 361.0.

[1513] Step 2: Synthesis of (3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1514] Pd(dppf)Cl ₂ to a solution of 4-bromo-3-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (670 mg, 1.87 mmol) bis(pinacolato)diboron (529 mg, 2.24 mmol), KOAc (548 mg, 5.6 mmol) in dioxane (10 mL) (300 mg, 0.4 mmol) was added. The mixture was degassed, charged with N ₂ three times, and stirred at 100° C. for 16 hours. The reaction was cooled to room temperature, concentrated and purified by column chromatography (PE/EA=10/1) to give (3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (500 mg, 66 % yield) as a yellow solid. LCMS (M+H ⁺ ) m/z : 407.1.

[1515] Step 3: Synthesis of 3-methyl-4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide formic acid

[1516] 디옥산 (10 mL) 및 물 (1 mL) 중 6-브로모-N-메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (150 mg, 0.54 mmol), 3-메틸-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-N-(4-(트리플루오로메틸) 피리딘-2-일)벤즈설폰아미드 (240 mg, 0.59 mmol), Cs ₂ CO ₃ (524 mg, 1.6 mmol) 및 Pd(dppf)Cl ₂ (40 mg, 0.06 mmol)의 혼합물을 탈기하고 N ₂ 로 3회 충전하고 100℃에서 16 시간 교반하였다. The reaction mixture was concentrated and purified by prep-HPLC (0.1% FA) to afford 3-methyl-4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide formic acid (7.0 mg, 3% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.26 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 8.25-8.18 (m, 1H), 7.95 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 4.8 Hz , 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.0 Hz , 1H), 7.17 (s, 1H), 4.03-3.89 (m, 4H), 2.84 (s, 3H), 2.31 (s, 3H). LCMS (M+H ⁺ ) m/z: 480.3.

Example 277: 2-fluoro-4-methyl-5- (2- (methylamino) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-6-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzsulfonamide (compound 277) manufacturing

[1517] Step 1: Synthesis of 5-bromo-2-fluoro-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1518] A mixture of 5-bromo-2-fluoro-4-methylbenzoic acid (546 mg, 2.35 mmol), 4-bromo-3-methylbenzoic acid (380 mg, 2.34 mmol), HATU (982 mg, 2.56 mmol) and DIEA (455 mg, 3.52 mmol) in DMF (10 mL) was stirred at 80 °C for 16 hours. The reaction was cooled to room temperature, diluted with water (50 mL), then extracted with EA (80 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over Na ₂ SO ₄ , filtered, concentrated and purified by column chromatography (PE/EA=10/1) to give 5-bromo-2-fluoro-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (530 mg, 60 % yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 377.0 and 379.0.

[1519] Step 2: 2-Fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1520] Pd(dppf)Cl ₂ to a solution of 5-bromo-2-fluoro-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (200 mg, 0.53 mmol), bis(pinacolato)diboron (150 mg, 0.64 mmol), KOAc (156 mg, 1.59 mmol) in dioxane (5 mL) (77 mg, 0.11 mmol) was added. The mixture was degassed, charged with N ₂ three times and stirred at 100° C. for 16 hours. The reaction was cooled to room temperature, concentrated and purified by column chromatography (PE/EA=10/1) to afford 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (120 mg, 53% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 425.1

[1521] Step 3: Synthesis of 2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1522] 디옥산 (15.0 mL) 및 물 (3 mL) 중 6-브로모-N-메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (110 mg, 0.39 mmol), 2-플루오로-4-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-N-(4-(트리플루오로메틸)피리딘-2-일)벤즈설폰아미드 (180 mg, 0.42 mmol), Cs ₂ CO ₃ (250 mg, 0.78 mmol) 및 Pd(dppf)Cl ₂ (32 mg, 0.04 mmol)의 혼합물을 탈기 및 충전하고 N ₂ 로 3회 충전하고 100℃ 16 시간 교반하였다. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative-TLC to afford 2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (20 mg, 10% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.24 (s, 1H), 8.65 (d, J = 5.2 Hz, 1H), 8.50 (s, 1H), 8.25 (d, J = 9.6 Hz, 1H), 7.58-7.23 (m, 5H), 4.08-3.89 (m , 4H), 2.85 (s, 3H), 2.30 (s, 3H). LCMS (M+H ⁺ ) m/z: 498.1.

Example 278: 2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (compound 278) manufacturing

[1523] Step 1: Synthesis of 5-bromo-2-fluoro-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1524] To a solution of 5-bromo-2-fluorobenzoic acid (0.5 g, 2.3 mmol) and 1 drop of DMF in DCM (8.0 mL), oxalyl chloride was added dropwise at 0°C. The reaction mixture was stirred for 2 hours and concentrated in vacuo to remove the solvent and used in the next step without further purification. A mixture of 5-bromo-2-fluorobenzoyl chloride (0.5 g, 2.3 mmol), DMAP (0.03 g, 0.23 mmol), 4-(trifluoromethyl)pyridin-2-amine (0.4 g, 2.4 mmol) and N,N-diisopropylethylamine (0.4 g, 2.7 mmol) in anhydrous THF (6.0 mL) was added subsequently. The reaction mixture was stirred and concentrated for 16 hours. H ₂ O (50 mL) was added and the mixture was extracted with EA (100 mL x 3). The combined organic phases were washed with brine (100.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA=3/1) to give 5-bromo-2-fluoro-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (566 mg, 68% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 362.9.

[1525] Step 2: Synthesis of 2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzsulfonamide

[1526] 5-bromo-2-fluoro-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (0.3 g, 0.8 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.6 g, 2.5 mmol) in dioxane (9.0 mL), KO To a mixture of Ac (0.2 g, 2.5 mmol) was added Pd(dppf)Cl ₂ (0.06 g, 0.1 mmol). The resulting mixture was degassed, charged with Ar three times, and stirred at 100°C for 3 hours. The reaction mixture was concentrated. H ₂ O (50.0 mL) was added and the mixture was extracted with EA (100 mL x 3). The combined organic phases were washed with brine (100.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA=10/1) to give 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (192 mg, 57% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 410.9.

[1527] Step 3: Synthesis of 2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide

[1528] 디옥산 (13.0 mL) 및 H ₂ O (1.3 mL) 중 2-플루오로-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-N-(4-(트리플루오로메틸)피리딘-2-일)벤즈설폰아미드 (0.2 g, 0.5 mmol), 6-브로모-N-메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘 -2-아민 (0.14 g, 0.5 mmol)의 혼합물에 Pd(dppf)Cl ₂ (0.04 g, 0.05 mmol), Cs ₂ CO ₃ (0.5 g, 1.4 mmol)를 첨가하였다. The resulting mixture was degassed, charged with N ₂ three times, and then stirred at 100° C. for 3 hours. The reaction mixture was concentrated. H ₂ O (50 mL) was added and the mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by trituration to afford 2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzsulfonamide (43 mg, 20% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.36 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 8.53 (s, 1H), 8.30-8.23 (m, 2H), 8.15-8.12 (m, 1H), 7.63 (s, 1H), 7 .56 (d, J = 4.8 Hz, 1H), 7.48–7.45 (m, 1H), 7.36 (t, J = 9.6 Hz, 1H), 4.07–3.97 (m, 4H), 2.84 (s, 3H). LCMS (M+H ⁺ ) m/z: 484.3.

Example 279: 2-fluoro-4-methyl-5- (2- (methylamino) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-6-yl) -N- (3- (trifluoromethyl) phenyl) benzsulfonamide (compound 279) manufacturing

[1529] Step 1: Synthesis of 5-bromo-2-fluoro-4-methyl-N-(3-(trifluoromethyl)phenyl)benzsulfonamide

[1530] A mixture of 5-bromo-2-fluoro-4-methylbenzoic acid (466 mg. 2 mmol), 3-(trifluoromethyl)aniline (354 mg, 2.2 mmol), HATU (836 mg, 2.2 mmol) and DIEA (390 mg, 3 mmol) in DMF (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (80 mL) and extracted with EA (100 mL x 3). The combined organic phases were washed with brine (50 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE/EA = 10/1) to give 5-bromo-2-fluoro-4-methyl-N-(3-(trifluoromethyl)phenyl)benzsulfonamide (526 mg, 70% yield)

[1531] Step 2: Synthesis of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethyl)phenyl)benzsulfonamide

[1532] To a mixture of 5-bromo-2-fluoro-4-methyl-N- (3- (trifluoromethyl) phenyl) benzsulfonamide (376 mg, 1 mmol) in dioxane (5 mL) 4,4,4', 4', 5,5,5', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (280 mg, 1.2 mmol), KOAc (6 50 mg, 6.6 mmol), Pd(dppf)Cl2 (160 mg, 0.22 mmol) were added. The mixture was degassed, charged with Ar three times, and stirred at 100° C. for 3 hours. The reaction mixture was concentrated in vacuo and H2O (50 mL) was added. The mixture was extracted with EA (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE/EA = 10/1) to give 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethyl)phenyl)benzsulfonamide (300 mg, 71% yield). LCMS (M+H+) m/z: 424

[1533] Step 3: Synthesis of 2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(3-(trifluoromethyl)phenyl)benzsulfonamide

[1534] 디옥산 (15.0 mL) 및 물 (3 mL) 중 6-브로모-N-메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (100 mg, 0.36 mmol), 2-플루오로-4-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-N-(3-(트리플루오로메틸)페닐)벤즈설폰아미드 (168 mg, 0.39 mmol), Cs ₂ CO ₃ (235 mg, 0.72 mmol) 및 Pd(dppf)Cl ₂ (58 mg, 0.07 mmol)의 혼합물을 탈기 및 충전하고 N ₂ 로 3회 충전하고 100℃에서 16 시간 교반하였다. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography to afford 2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(3-(trifluoromethyl)phenyl)benzsulfonamide (60 mg, 60% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.66 (s, 1H), 8.22-8.17 (m, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.4 4 (d, J = 7.6 Hz, 2H), 7.26 (d, J = 7.6 Hz, 1H), 7.17 (s, 1H), 4.02–3.87 (m, 4H), 2.82 (s, 3H), 2.29 (s, 3H). LCMS (M+H ⁺ ) m/z: 497.0.

Example 280: 2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(3-(trifluoromethyl)phenyl)benzsulfonamide (compound 280) manufacturing

[1535] Step 1: Synthesis of 2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(3-(trifluoromethyl)phenyl)benzsulfonamide

[1536] 2-Fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzoic acid (30 mg, 0.084 mmol, 1.0 eq) and 3-(trifluoromethyl)aniline in DMF (2 mL) (16 mg, 0.10 mmol, and 1.2 eq) was added DIEA (0.1 mL) and HATU (64 mg, 0.117 mmol, 2.0 eq). The mixture was stirred overnight at 20 °C. LCMS results indicated that the reaction performed well. The crude was diluted with H ₂ O (30 mL) and extracted twice with EA (30 mL). The pooled extracts were washed with brine (20 mL). Concentration and purification by preparative-HPLC (0.1% HCl) afforded 2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-N-(3-(trifluoromethyl)phenyl)benzsulfonamide (4.2 mg, 10.1% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.83 (d, J = 4.4 Hz, 1H), 10.22-10.21 (m, 1H), 8.98-8.88 (m, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.22 (s, 2H), 7.98 (d, J = 8.4 Hz, 1H), 7.78-7.74 (m, 1H), 7.63-7.59 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 4.69-4.62 (m, 2H), 4.09-4.05 (m, 2H), 2.98 (s, 3H), 2.29 (s, 3H). LCMS (M+H ⁺ ) m/z: 497.1.

Example 281: N-(3- Chloro -4-(2-( methylamino )-9,10- dihydro -8H- Pyrido[1,6-a:2,3-d']dipyrimidine -6-yl) pyridin-2-yl) furan-3-sulfonamide (compound 281) manufacturing

[1537] The preparation of tert-butyl (6-(2,3-dichloropyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)(methyl)carbamate is described in Example 74.

[1538] Step 1: Synthesis of furan-3-sulfonamide

[1539] To a solution of furan-3-sulfonyl chloride (200 mg, 1.2 mmol) in MeOH (3 mL) was added NHOH (3 mL). The mixture was stirred at 0 °C for 16 hours. The pH was adjusted to 7 with 2N HCl. The mixture was extracted with EtOAc (2 Х10 mL) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product furan-3-sulfonamide (120 mg, 46.5 % yield) as a white solid. LCMS (M+H+) m/z: 148.1

[1540] Step 2: Synthesis of tert-butyl (6-(3-chloro-2-(furan-3-sulfonamido)pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)(methyl)carbamate

[1541] To a solution of tert-butyl (6-(2,3-dichloropyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)(methyl)carbamate (120 mg, 0.26 mmol) in dioxane (5 mL) was added furan-3-sulfonamide (120 mg, 0.82 mmol), RuPhos Pd G4 (14 mg, 0.016 mmol) and Cs2CO3 (310 mg, 1.02 mmol) were added. The mixture was stirred at 100° C. for 16 hours. The mixture was extracted with EtOAc (2 Х 10 mL) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield the crude product tert-butyl (6-(3-chloro-2-(furan-3-sulfonamido)pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidine -2-yl)(methyl)carbamate (60 mg, crude) was obtained as a yellow oil. LCMS (M+H+) m/z: 571.9

[1542] Step 3: Synthesis of N-(3-chloro-4-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)pyridin-2-yl)furan-3-sulfonamide

[1543] To a solution of tert-butyl (6-(3-chloro-2-(furan-3-sulfonamido)pyridin-4-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-yl)(methyl)carbamate (60 mg, crude) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 2 hours. Concentration gave the crude product, which was purified by preparative-HPLC (NH4HCO3) and preparative-HPLC (0.1% FA) to N-(3-chloro-4-(2-(methylamino)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-6-yl)pyridin-2-yl)furan-3-sulfonamide (2 mg, 4.8% yield) was obtained as a yellow solid. ¹ HNMR (400 MHz, CD ₃ OD): δ 8.64 (s, 1H), 7.98 (d, J = 4.8 Hz, 1H), 7.93 (s, 1H), 7.75 (s, 1H), 7.37-7.36 (m, 1H), 6.73 (d, J = 1.2 Hz, 1H), 6 .56 (d, J = 4.8 Hz, 1H), 4.68–4.41 (m, 2H), 3.46–3.41 (m, 2H), 2.98 (s, 3H), 2.16–2.14 (m, 2H). LCMS (M+H ⁺ ) m/z: 472.0.

Example 282 N-(2- methoxy -5-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)pyridin-3-yl)methanesulfonamide (Compound 282)

[1544] Step 1: Synthesis of N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide

[1545] A mixture of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (600 mg, 2.4 mmol, 1.0 eq) and MsCl (0.5 mL) in pyridine (5 mL) was stirred at room temperature for 0.5 h. The mixture was concentrated. Water (30 mL) was added and the reaction mixture was extracted twice with EA (50 mL). The combined organic phases were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (600 mg) as a yellow solid. LCMS (M+H ⁺ ) m/z: 329.2

[1546] Step 2: Synthesis of N-(2-methoxy-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)pyridin-3-yl)methanesulfonamide

[1547] 디옥산 (20 mL) 및 H ₂ O (1.5 mL) 중 N-(2-메톡시-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)피리딘-3-일)메탄설폰아미드 (117 mg, 0.36 mmol, 1.0 eq), 6-브로모-N-메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (100 mg, 0.36 mmol, 1.0 eq), K ₂ CO ₃ (150 mg, 1.07 mmol, 3.0 eq) 및 Pd (dppf)Cl ₂ (26 mg, 0.036 mmol)의 혼합물을 100℃에서 3시간 교반하였다. The mixture was purified by preparative-HPLC (0.1% FA and 0.1% NH ₄ HCO ₃ ) to afford N-(2-methoxy-5-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)pyridin-3-yl)methanesulfonamide (2.1 mg) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.07 (br s, 1H), 9.44-9.41 (m, 1H), 8.70 (s, 1H), 8.25-8.21 (m, 1H), 8.02-7.84 (m, 2H), 4.49-4.43 (m, 2H), 4.05-3.98 (m, 5H), 3.09 (s, 3H), 2.93-2.9-87 (m, 3H). LCMS (M+H ⁺ ) m/z: 402.2.

Example 283 N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzenesulfonamide (Compound 283)

[1548] Step 1: Synthesis of N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzenesulfonamide

[1549] 3-(trifluoromethyl)benzenesulfonyl chloride (17 mg, 0 .08 mmol) was added at 0° C. under N ₂ . The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by prep-HPLC (0.1% NH ₃ ^. H ₂ O) to afford N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzenesulfonamide (4.9 mg, 10% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.31 (br, 1H), 8.22 (br, 1H), 8.03-8.01 (m, 3H), 7.82 (t, J = 8.0 Hz, 1H), 7.62-7.34 (m, 1H), 7.11 (d, J = 8.0 Hz , 1H), 6.97–6.94 (m, 3H), 4.12–3.95 (m, 2H), 3.89–3.85 (m, 2H), 2.85 (s, 3H), 2.10 (s, 3H). LCMS (M+H ⁺ ) m/z: 515.2.

Example 284 N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide (Compound 284)

[1550] Step 1: Synthesis of 2-fluoro-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide

[1551] To a mixture of 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.196 mmol) in pyridine (10 mL) was added 2-(trifluoromethyl)benzenesulfonyl chloride (143 mg, 0.588 mmol) at room temperature , the mixture was stirred at 55 °C for 2 h. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=10/1) to give the crude product which was purified by preparative-HPLC (0.1% NH ₃ ^.H ₂ O) to obtain 2-fluoro-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl ) Benzenesulfonamide (43.6 mg, 43% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.29 (s, 1H), 8.17-8.14 (m, 1H), 8.01-7.96 (m, 3H), 7.77 (t, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.01 (d, J = 8.0 Hz) , 1H), 6.88–6.87 (m, 3H), 4.01–3.96 (m, 2H), 3.87 (t, J = 8.8 Hz, 2H), 2.83 (s, 3H), 2.08 (s, 3H). LCMS (M+H ⁺ ) m/z: 515.6.

Example 285: N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzenesulfonamide (compound 285) manufacturing

[1552] Step 1: Synthesis of N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)-N-((3-(trifluoromethyl)phenyl)sulfonyl)benzenesulfonamide

[1553] 3-(trifluoromethyl)benzenesulfonyl chloride in a solution of 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.20 mmol), DIEA (53 mg, 0.41 mmol) in DCM (5.0 mL) (198 mg, 0.61 mmol) was added at room temperature under N ₂ . The resulting mixture was stirred at 80° C. for 16 h under N ₂ . The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=10/1) to N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)-N-((3-(trifluoromethyl)phenyl)sulfonyl)benzenesulfone. The amide (40 mg, 27% yield) was obtained as a brown solid. LCMS (M+H ⁺ ) m/z: 740.8.

[1554] Step 2: Synthesis of N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzenesulfonamide

[1555] N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)-N-((3-(trifluoromethyl)phenyl)sulfonyl)benzenesulfonamide (40 mg, 0.054 mmol) was added TBAF (12 mg, 0.054 mmol) at room temperature for 0.5 h under N ₂ . The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (DCM/MeOH=10/1) to give the crude product which was purified by Pre-HPLC (0.1% FA) to N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzene Gensulfonamide (5.0 mg, 17.5% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.20 (br s, 1H), 8.29-8.28 (m, 1H), 8.01-7.98 (m, 3H), 7.79-7.75 (m, 1H), 7.65-7.52 (m, 1H), 7.05-6.99 ( m, 3H), 4.15–4.11 (m, 2H), 3.92–3.88 (m, 2H), 2.86 (s, 3H), 2.12 (s, 3H). LCMS (M+H ⁺ ) m/z: 533.2.

Example 286:2 - Chloro -N-(2- Fluoro -4- methyl -5-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (Compound 286)

[1556] Step 1: Synthesis of 2-chloro-N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide

[1557] To a mixture of 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (100 mg, 0.31 mmol) in pyridine (10 mL) was added 2-chlorobenzenesulfonyl chloride (200 mg, 0.93 mmol) at room temperature, The mixture was stirred at 40 °C for 2 hours. The reaction mixture was concentrated and purified by prep-HPLC (0.1% NH3.H2O) to afford 2-chloro-N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (22.0 mg, 13% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.16-8.15 (m, 1H), 7.88 (dd, J = 7.6, 1.6 Hz, 1H), 7.49-7.42 (m, 2H), 7.40-7.33 (m, 2H), 7.10-6.94 (m, 2H), 6.83–6.80 (m, 2H), 4.01–3.94 (m, 2H), 3.86 (t, J = 8.4 Hz, 2H), 2.83 (d, J = 4.4 Hz, 3H), 2.04 (s, 3H). LCMS (M+H ⁺ ) m/z: 499.1.

Example 287: 2 - Chloro -N-(2- Fluoro -4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (Compound 287)

[1558] Step 1: Synthesis of 2-chloro-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide

[1559] To a solution of 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 0.123 mmol) in pyridine (3 mL) was added 2-chlorobenzenesulfonyl chloride (52 mg, 0.247 mmol). The reaction was stirred at 50 °C for 2 hours. Removal of solvent followed by purification by prep-HPLC (0.1% TFA) afforded 2-chloro-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide as a white solid (4.1 mg, 10% yield). ^1H NMR (400 MHz, CD ₃ OD): δ 8.77 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.99 (s, 1H), 7.60 (d, J = 3.6 Hz, 2H), 7.47-7.39 (m, 2H), 7.13 (d, J = 8.4 Hz , 1H), 4.78 (t, J = 10.0 Hz, 2H), 4.12 (t, J = 10.0 Hz, 2H), 3.09 (s, 3H), 2.19 (s, 3H). LCMS (M+H ⁺ ) m/z: 499.1.

Example 288: N-(2- Fluoro -4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide (compound 288) manufacturing

[1560] Step 1: Synthesis of N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide

[1561] To a solution of 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 0.12 mmol) in pyridine (4 mL) was added propane-1-sulfonyl chloride (20 mg, 1.1 mmol) at 20°C. The reaction mixture was stirred at 50 °C for 2 hours. LCMS results indicated that the reaction performed well. The reaction mixture was concentrated in vacuo and purified by prep-HPLC (0.1% HCl) to give N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide (4.4 mg, 8%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.71 (s, 1H), 8.02 (s, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.73-4.68 (m, 2H), 4.08-4.03 (m, 2 H), 3.05–2.99 (m, 5H), 2.15 (s, 3H), 1.79–1.73 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). LCMS (M+H ⁺ ) m/z: 431.2.

Example 289: 2 - Fluoro -N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (compound 289) manufacturing

[1561] Step 1: Synthesis of 2-fluoro-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide

[1563] To a mixture of 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (100 mg, 0.33 mmol) in pyridine (10 mL) was added 2-fluorobenzenesulfonyl chloride (190 mg, 0.98 mmol) at room temperature and the mixture at room temperature Stir for 2 hours. The reaction mixture was concentrated and purified by prep-HPLC (0.1% NH ₃ ^. H ₂ O) to afford 2-fluoro-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (55.1 mg, 36% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.42-8.41 (m, 1H), 8.14 (s, 1H), 7.85-7.81 (m, 1H), 7.73-7.67 (m, 2H), 7.45-7.35 (m, 3H), 7.12-7.11 (m, 1 H), 7.03–7.01 (m, 2H), 4.25–4.08 (m, 2H), 3.90 (t, J = 8.8 Hz, 2H), 2.87 (s, 3H), 2.08 (s, 3H). LCMS (M+H ⁺ ) m/z: 465.2.

Example 290:2 ,6- difluoro -N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (compound 290) manufacturing

[1564] Step 1: Synthesis of 2,6-difluoro-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide

[1565] To a mixture of 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.16 mmol) in pyridine (1.5 mL) was added 2,6-difluorobenzenesulfonyl chloride (104 mg, 0.49 mmol). The mixture was stirred at 50 °C for 2 hours. The reaction mixture was concentrated and purified by column chromatography on silica gel (DCM: MeOH= 20:1) to give the crude product which was further purified by preparative-HPLC (0.1% NH ₃ H ₂ O) to give 2,6-difluoro-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl )Phenyl)benzenesulfonamide (27.6 mg, 25% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.75 (s, 1H), 8.22-8.19 (m, 1H), 7.70-7.67 (m, 1H), 7.44-7.42 (m, 1H), 7.26 (t, J = 8.8 Hz, 2H), 7.08 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.94 (s, 2H), 4.01-3.96 (m, 2H), 3.86 (t, J = 8.8 Hz, 2H), 2.84 (d, J = 3.6 Hz, 3H), 2.10 (s, 3H). LCMS (M+H ⁺ ) m/z: 483.2.

Example 291:2 ,5- difluoro -N-(4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (compound 291) manufacturing

[1566] Step 1: Synthesis of 2,5-difluoro-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide

[1567] To a mixture of 6-(5-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (80 mg, 0.26 mmol) in pyridine (10 mL) was added 2,5-difluorobenzenesulfonyl chloride (167 mg, 0.78 mmol) at room temperature and the mixture It was stirred for 2 hours at 40°C. The reaction mixture was concentrated and purified by prep-HPLC (0.1% NH ₃ ^. H ₂ O) to afford 2,5-difluoro-N-(4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (27.3 mg, 21.8% yield) as a yellow solid. did ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.63 (s, 1H), 8.22-8.19 (m, 1H), 7.62-7.42 (m, 4H), 7.09 (d, J = 8.4 Hz, 1H), 6.99-6.96 (m, 3H), 4.07-3.96 (m, 2H), 3.87 (t, J = 8.8 Hz, 2H), 2.83 (d, J = 3.6 Hz, 3H), 2.10 (s, 3H). LCMS (M+H ⁺ ) m/z: 483.7.

Example 292 N-(2- Fluoro -4- methyl -5-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)pyridine-2-sulfonamide (compound 292) manufacturing

[1568] Step 1: Synthesis of N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)pyridine-2-sulfonamide

[1569] To a mixture of 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.15 mmol) in pyridine (1.5 mL) was added pyridine-2-sulfonyl chloride (137 mg, 0.77 mmol). The mixture was stirred at 50 °C for 2 hours. The reaction mixture was concentrated and purified by column chromatography on silica gel (DCM:MeOH= 20:1) to give the crude product which was further purified by preparative-HPLC (0.1% HCOOH) to N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)pyridin-2- Sulfonamide (33.8 mg, 47% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.72 (d, J = 4.0 Hz, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 8.07-8.02 (m, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.67-7.64 (m, 1H), 7.49-7.44 (m, 1H), 7.06-7.01 (m, 3H), 4.06-3.90 (m, 2H), 3.86 (t, J = 9.6 Hz, 2H), 2.85 (d, J = 4.4 Hz, 3H), 2.14 (s, 3H). LCMS (M+H ⁺ ) m/z: 466.2.

Example 293 N-(2- Fluoro -4- methyl -5-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)-1-phenylmethanesulfonamide (Compound 293)

[1570] Step 1: Synthesis of N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-1-phenylmethanesulfonamide

[1571] To a mixture of 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.15 mmol) in pyridine (1.5 mL) was added phenylmethanesulfonyl chloride (88 mg, 0.46 mmol). The mixture was stirred at 50 °C for 2 hours. The reaction mixture was concentrated and purified by column chromatography on silica gel (DCM:MeOH= 20:1) to give the crude product which was further purified by preparative-HPLC (0.1% HCOOH) to obtain N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-1-phenylmethane Sulfonamide (22.4 mg, 30% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.41 (s, 1H), 8.14 (s, 1H), 7.36-7.33 (m, 5H), 7.29-7.18 (m, 3H), 7.08 (d, J = 8.4 Hz, 1H), 4.47 (s, 2H), 4. 24-4.07 (m, 2H), 3.93 (t, J = 8.8 Hz, 2H), 2.88 (s, 3H), 2.19 (s, 3H). LCMS (M+H ⁺ ) m/z: 479.2.

Example 294:2 - Fluoro -N-(2- Fluoro -4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (Compound 294)

[1572] Step 1: Synthesis of 2-fluoro-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide formate

[1573] To a solution of 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.15 mmol, 1.0 eq) in DCM (5 mL) was added pyridine (0.1 mL) and 2-fluorobenzenesulfonyl chloride (58 mg , 0.3 mmol, 2.0 eq) was added. The mixture was stirred at 20° C. under N2 for 16 hours. LCMS results indicated that the reaction performed well. Concentrated in vacuo and purified by prep-HPLC (0.1% FA) to afford 2-fluoro-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide formate (7.2 mg, 6.4%) as a yellow solid. ^1H NMR (400 MHz, CD ₃ OD): δ 8.40 (s, 1H), 7.80-7.77 (m, 1H), 7.66-7.60 (m, 1H), 7.43-7.27 (m, 4H), 7.04-7.02 (m, 1H), 4.44-4.37 (m, 2H) ), 4.02–3.97 (m, 2H), 3.01 (s, 3H), 2.16 (s, 3H). LCMS (M+H ⁺ ) m/z: 483.0.

Example 295:2 ,5- difluoro -N-(2- Fluoro -4- methyl -3-(2-( methylamino )-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (compound 295) manufacturing

[1574] Step 1: Synthesis of 2,5-difluoro-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide

[1575] To a solution of 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (20 mg 0.077 mmol) in pyridine (2 mL) was added 2,5-difluorobenzenesulfonyl chloride (33mg, 0.154mmol) . The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was purified by preparative-HPLC (0.1% TFA) to afford 2,5-difluoro-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (10.8 mg, 35.1% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.69 (s, 1H), 9.85 (s, 1H), 8.84 (s, 1H), 8.58-8.56 (m, 1H), 8.06 (s, 1H), 7.62-7.53 (m, 3H), 7.28 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 4.63–4.60 (m, 2H), 4.00–3.98 (m, 2H), 2.96 (d, J = 4.8 Hz, 3H), 2.14 (s, 3H). LCMS (M+H ⁺ ) m/z: 501.0.

Example 296:2 ,6- dichloro -N-(2- Fluoro -4- methyl -3-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (compound 296) manufacturing

[1576] Step 1: Synthesis of 2,6-dichloro-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide

[1577] To a mixture of 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (30 mg, 0.093 mmol, 1 eq) in DCM (5 mL) was added pyridine (1 mL) and 2,6-dichlorobenzenesulfonyl chloride (46 mg, 0.186 mmol, 2 eq) was added. The mixture was stirred at room temperature under N2 for 3 hours. The resulting mixture was purified by preparative-HPLC (0.1% NH3.H2O) to afford 2,6-dichloro-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (3.8 mg, 7.9% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.33 (s, 1H), 7.51-7.48 (m, 2H), 7.41-7.37 (m, 1H), 7.26 (t, J = 8.0 Hz, 2H), 6.97 (d, J = 8.8 Hz, 1H), 4.36-4.42 (m, 2H), 4.00–3.96 (m, 2H), 2.99 (s, 3H), 2.15 (s, 3H). LCMS (M+H ⁺ ) m/z: 533.0.

Example 297:2 ,6- difluoro -N-(2- Fluoro -4- methyl -3-(2-( methylamino )-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (compound 297) manufacturing

[1578] Step 1: Synthesis of 2,6-difluoro-N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide

[1579] To a mixture of 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (30 mg, 0.093 mmol, 1 eq) in DCM (5 mL) was added pyridine (1 mL) and 2,6-difluorobenzenesulfonyl chloride (40 mg , 0.186 mmol, 2 eq) was added. The mixture was stirred at room temperature under N2 for 3 hours. The obtained mixture is purified by sorky-HPLC (0.1% nh3.h2o) and 2,6-defluoro-N- (2-fluoro-4-methyl-3- (2- (methylamino) -8,9-dihydro) already Dazo [1 ', 2': 1,6] Pyrido [2, 3-D] Pyrimidin-6-yl) 2.6 mg, 5.6% yield) was obtained as a yellow solid. ^1H NMR (400 MHz, CD ₃ OD): δ 8.37 (s, 1H), 7.52-7.48 (m, 1H), 7.36-7.26 (m, 4H), 7.00 (d, J = 8.0 Hz, 1H), 4.41-4.36 (m, 2H), 4.01-3.96 (m, 2H), 3.00 (s, 3H), 2.16 (s, 3H). LCMS (M+H ⁺ ) m/z: 501.0.

Example 298: N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide (compound 298) manufacturing

[1580] Step 1: Synthesis of N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide

[1581] To a mixture of 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 0.12 mmol) in pyridine (2 mL) was added 2-(trifluoromethyl)benzenesulfonyl chloride (60 mg, 0.24 mmol) . The mixture was stirred at 20 °C for 16 hours. Concentration and purification by preparative-HPLC (0.1% NH3.H2O) afforded N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide (1.0 mg, 2% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.31(s, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.76-7.66 (m, 2H), 7.30-7.26 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H), 4.90–4.88 (m, 2H), 4.00–3.96 (m, 2H), 2.99 (s, 3H), 2.16 (s, 3H). LCMS (M+H ⁺ ) m/z: 533.0.

Example 299: N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethoxy)benzenesulfonamide (compound 299) manufacturing

[1582] Step 1: Synthesis of N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethoxy)benzenesulfonamide

[1583] To a mixture of 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 0.12 mmol) in pyridine (2 mL), 2-(trifluoromethoxy)benzenesulfonyl chloride (60 mg, 0.24 mmol) was added. added. The mixture was stirred at 20 °C for 16 hours. Concentration and purification by preparative-HPLC (0.1% NH3.H2O) afforded N-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-(trifluoromethoxy)benzenesulfonamide (2.1 mg, 3% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.27 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.70-7.66 (m, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.18-7.16 (m, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.30-4.25 (m, 2H), 3.96 (t, J = 10.0 Hz, 2H), 2.99 (s, 3H) , 2.15 (s, 3H). LCMS (M+H ⁺ ) m/z: 549.0.

Example 300: 2-Fluoro-N-(2-fluoro-4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (compound 300) manufacturing

[1584] Step 1: Synthesis of 2-fluoro-N-(2-fluoro-4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide

[1585] To a solution of 6-(3-amino-2-fluoro-6-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 0.1 mmol, 1.0 eq) in DCM (5 mL) was added pyridine (0.1 mL) and 2 -Fluorobenzenesulfonyl chloride (30 mg, 0.15 mmol, 1.5 eq) was added. The mixture was stirred at 20° C. under N ₂ for 16 h. LCMS results indicated that the reaction performed well. Concentrated in vacuo and purified by prep-HPLC (0.1% TFA) to obtain 2-fluoro-N-(2-fluoro-4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (9.0 mg, 16% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.87 (s, 1H), 8.04-8.03 (m, 2H), 7.85-7.63 (m, 3H), 7.46-7.42 (m, 1H), 7.32-7.27 (m, 2H), 7.16-7.14 (m, 1H) ), 4.91–4.82 (m, 2H), 4.18–4.11 (m, 2H), 3.90 (s, 3H), 2.20 (s, 3H). LCMS (M+H ⁺ ) m/z: 549.5.

Example 301: 2,5-difluoro-N-(2-fluoro-4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (compound 301) manufacturing

[1586] Step 1: Synthesis of 2,5-difluoro-N-(2-fluoro-4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide

[1587] To a solution of 6-(3-amino-2-fluoro-6-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.15 mmol, 1.0 eq) in DCM (5 mL) was added pyridine (0.1 mL) and 2,5-difluorobenzenesulfonyl chloride (65 mg, 0.3 mmol, 2 eq) was added. The mixture was stirred at 20° C. under N2 for 16 hours. LCMS results indicated that the reaction performed well. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1% TFA) to give 2,5-difluoro-N-(2-fluoro-4-methyl-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (14.1 mg, 17% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.88 (s, 1H), 8.06-8.04 (m, 2H), 7.77 (s, 1H), 7.57-7.53 (m, 1H), 7.47-7.39 (m, 3H), 7.20-7.18 (m, 1H), 4. 91-4.88 (m, 2H), 4.18-4.11 (m, 2H), 3.89 (s, 3H), 2.20 (s, 3H). LCMS (M+H ⁺ ) m/z: 567.4.

Example 302: 2,5-difluoro-N-(2-fluoro-4-methyl-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (compound 302) manufacturing

[1588] Step 1: Synthesis of 2-fluoro-4-methyl-3- (2- (methylthio) -8, 9-dihydroimidazo [1 ', 2': 1, 6] pyrido [2, 3-d] pyrimidin-6-yl) benzonitrile

[1589] _2- fluoro-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa Borolan-2-yl)benzonitrile (760 mg, 2.90 mmol), Cs ₂ CO ₃ (2.2 g, 6.69 mmol), Ruphos (210 mg, 0.446 mmol) and Pd-X-phos G3 (380 mg, 0.446 mmol) were added. The reaction mixture was stirred at 110° C. under N ₂ for 16 hours. Concentration in vacuo and purification by silica gel column chromatography (DCM/MeOH=10:1) gave 2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)benzonitrile (0.7 g, 89.4% yield) as a yellow solid.

[1590] Step 2: Synthesis of methyl 2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzoate

[1591] To a solution of 2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzonitrile (0.7 g, 1.99 mmol) in MeOH (15 mL) was added H2SO4 (3 mL) and the reaction mixture was heated at 100 °C. Stir for 36 hours in a sealed test tube. Concentration in vacuo and purification by column chromatography (0.1% NH3H2O) afforded methyl 2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzoate (300 mg, 39.2% yield) as a yellow solid.

[1592] Step 3: 2-fluoro-4-methyl-3- (2- (methylthio) -8, 9-dihydroimidazo [1 ', 2': 1, 6] pyrido [2, 3-d] pyrimidin-6-yl) synthesis of benzoic acid

[1593] LiOH (66 mg, 1.56 mmol) to a solution of methyl 2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)benzoate (300 mg, 0.78 mmol) in MeOH/HO (5 mL/5 mL) ) was added. The reaction mixture was stirred at room temperature for 3 hours, concentrated in vacuo and purified by column chromatography to afford 2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)benzoic acid (210 mg, 72.8% yield) as a yellow solid.

[1594] Step 4: Synthesis of tert-butyl (2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate

[1595] DPPA (314 mg, 1.14 mmol) and TEA ( 172 mg, 1.71 mmol) was added. The reaction mixture was stirred at 90 °C for 16 hours. Concentration in vacuo afforded tert-butyl (2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (300 mg, crude) as a yellow solid which was used directly in the next step.

[1596] Step 5: Synthesis of 2-fluoro-4-methyl-3- (2- (methylthio) -8, 9-dihydroimidazo [1 ', 2': 1, 6] pyrido [2, 3-d] pyrimidin-6-yl) aniline

[1597] A solution of tert-butyl (2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (300 mg, crude) in MeOH/HCl (5 mL) was stirred at room temperature for 16 hours. Concentration in vacuo and purification on column chromatography gave 2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)aniline (120 mg, 45.1% yield) as a yellow solid.

[1598] Step 6: Synthesis of 2,5-difluoro-N-(2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide

[1599] 2,5-difluorobenzenesulfonyl chloride (75 mg, 0.35 mg, 0.35 2 mmol) and pyridine (0.5 mL) were added. The reaction was stirred at room temperature for 16 hours. The resulting mixture was purified by column chromatography to afford 2,5-difluoro-N-(2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (45 mg, 22.3% yield) as a yellow solid.

[1600] Step 7: Synthesis of 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo [1', 2': 1, 6] pyrido [2, 3-d] pyrimidine

[1601] m-CPBA (3 8 mg, 0.218 mmol, 2.5 eq) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. Oxetan-3-amine (32 mg, 0.437 mmol, 5.0 eq) was then added and the reaction mixture was stirred at 20° C. for 16 h. LCMS showed the reaction to be complete. The reaction mixture was diluted with DCM (50 mL) and washed with H ₂ O (50 mL), brine (20 mL). Concentrated in vacuo and purified by preparative-HPLC (0.1% NH ₃ ^. H ₂ O) to afford 6-bromo-2-(methylsulfinyl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine (4.1 mg, 10.8% yield) as a yellow solid. ^1H NMR (400 MHz, CD ₃ OD): δ 8.32 (s, 1H), 7.51-7.47 (m, 1H), 7.36-7.24 (m, 4H), 7.00 (d, J = 8.4 Hz, 1H), 5.12 (t, J = 7.2 Hz, 1H), 4.95 (t, J = 6.8 Hz, 2H), 4.68 (t, J = 6.8 Hz, 2H), 4.26 (t, J = 9.6 Hz, 2H), 3.97 (t, J = 10.0 Hz, 2H), 2.16 (s, 3H). LCMS (M+H ⁺ ) m/z: 543.1.

Example 303: 2 - Chloro -N-(2- Fluoro -4- methyl -3-(2-( oxetane -3- ylamino )-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (compound 303) manufacturing

[1602] Step 1: Synthesis of 2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)aniline

[1603] 2-chlorobenzenesulfonyl chloride (74 mg, 0.352 mmol , 2.0 eq) and pyridine (0.2 mL) were added. The mixture was stirred at 20 °C for 3 hours. LCMS results indicated that the reaction performed well. The reaction mixture was dissolved with DCM (50 mL) and washed with H ₂ O (50 mL), brine (20 mL). Concentrated in vacuo and purified by preparative-HPLC (0.1% NH ₃ ^. H ₂ O) to afford 2-fluoro-4-methyl-3-(2-(methylthio)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)aniline (45 mg, 49.6% yield) as a yellow solid.

[1604] Step 2: Synthesis of 2-chloro-N-(2-fluoro-4-methyl-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo [1',2':1,6] pyrido [2,3-d] pyrimidin-6-yl) phenyl) benzenesulfonamide

[1605] m-CPBA (38 mg, 0.218 mmol, 0.218 mmol, 2.5 eq) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. Oxetan-3-amine (32 mg, 0.437 mmol, 5.0 eq) was then added and the reaction mixture was stirred at 20° C. for 16 h. LCMS showed the reaction to be complete. The reaction mixture was diluted with DCM (50 mL) and washed with H ₂ O (50 mL), brine (20 mL). Concentration in vacuo and purification by preparative-HPLC (0.1% NH3.H2O) afforded 2-chloro-N-(2-fluoro-4-methyl-3-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (5.1 mg, 10.8% yield). Obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.23 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.56-7.52 (m, 2H), 7.42-7.38 (m, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.12 (s, 1H), 6.95 (d, J = 8.8 Hz, 1H), 5.13-5.09 (m, 1H), 4.94 (t, J = 6.8 Hz, 2H), 4.67 (t, J = 6.4 Hz, 2H), 4.19 (t, J = 9.6 Hz, 2H), 3.94 (t, J = 10.0 Hz, 2H), 2.13 (s, 3H). LCMS (M+H ⁺ ) m/z: 541.1.

Example 304 N-(4-((2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)oxy)phenyl)-4-(trifluoromethyl)picolinesulfonamide (compound 304) manufacturing

[1606] Step 1: Synthesis of ethyl 2-(4-nitrophenoxy)acetate

[1607] A mixture of 4-nitrophenol (14 g, 100 mmol), ethyl 2-bromoacetate (16.7 g, 100 mmol) and K ₂ CO ₃ (34.5 g, 250 mmol) in MeCN (180 mL) was stirred at 85 °C for 3 hours. The reaction was filtered and concentrated to give ethyl 2-(4-nitrophenoxy)acetate (18.6 g) as a solid. LCMS (M+H ⁺ ) m/z: 225.9

[1608] Step 2: Synthesis of 2-(methylthio)-6-(4-nitrophenoxy)pyrido[2,3-d]pyrimidin-7(8H)-one

[1609] A mixture of ethyl 2-(4-nitrophenoxy)acetate (4.22 g, 20 mmol), 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (3.40 g, 20 mmol), K2CO3 (8.28 g, 60 mmol) in NMP (60 mL) was stirred at 120°C for 16 hours. The reaction was filtered, poured into water, and the pH was adjusted to 7 with 2N HCl. The obtained solid was filtered and dried to give 2-(methylthio)-6-(4-nitrophenoxy)pyrido[2,3-d]pyrimidin-7(8H)-one (3.8 g) as an orange solid. LCMS (M+H ⁺ ) m/z: 330.9

[1610] Step 3: Synthesis of 7-chloro-2-(methylthio)-6-(4-nitrophenoxy)pyrido[2,3-d]pyrimidine

[1611] To a mixture of 2-(methylthio)-6-(4-nitrophenoxy)pyrido[2,3-d]pyrimidin-7(8H)-one (2.0 g, 6.0 mmol) was added POCl ₃ (12.0 mL) at room temperature. The reaction mixture was stirred at 110° C. for 5 hours. The reaction mixture was concentrated and poured into NaHCO ₃ aq and extracted with EA (100 mL x 2). The combined organic phases were washed with water, dried over Na ₂ SO ₄ , and concentrated to give 7-chloro-2-(methylthio)-6-(4-nitrophenoxy)pyrido[2,3-d]pyrimidine (1.2 g, 60% yield) as a white solid. LCMS (M+H ⁺ ) m/z 348.9.

[1612] Step 4: Synthesis of 2-((2-(methylthio)-6-(4-nitrophenoxy)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol

[1613] A mixture of 7-chloro-2-(methylthio)-6-(4-nitrophenoxy)pyrido[2,3-d]pyrimidine (1.0 g, 3.0 mmol) and ethanolamine (720 mg, 12.0 mmol) in i-PrOH (20 mL) was stirred at 80° C. for 3 hours. The reaction was concentrated and purified by flash (PE: EA=3:1) to afford 2-((2-(methylthio)-6-(4-nitrophenoxy)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (860 mg, 77% yield) as a solid. LCMS (M+H ⁺ ) m/z: 373.9

[1614] Step 5: Synthesis of 2-(methylthio)-6-(4-nitrophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[1615] To a mixture of 2-((2-(methylthio)-6-(4-nitrophenoxy)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (370 mg, 1.0 mmol) in CHCl ₃ (10 mL) was added SOCl ₂ (360 mg, 3.0 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 2 hours. The reaction was concentrated and flash purified (PE: EA=3: 1) to give 2-(methylthio)-6-(4-nitrophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (260 mg, 73% yield) as a solid. LCMS (M+H ⁺ ) m/z: 355.9.

[1616] Step 6: Synthesis of 2-(methylsulfinyl)-6-(4-nitrophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[1617] To a mixture of 2-(methylthio)-6-(4-nitrophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (520 mg, 1.5 mmol) in DCM (20 mL) was added m-CPBA (645 mg, 3.75 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 3 hours. The reaction was concentrated and flash purified (DCM: methanol = 40: 1) to give 2-(methylsulfinyl)-6-(4-nitrophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (430 mg, 77% yield) as a solid. LCMS (M+H ⁺ ) m/z: 371.9.

[1618] Step 7: Synthesis of N-methyl-6-(4-nitrophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1619] To a mixture of 2-(methylsulfinyl)-6-(4-nitrophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (430 mg, 1.15 mmol) in THF (2.0 mL) was added 30% MeNH ₂ in ethanol (2.0 mL) at room temperature. The reaction mixture was stirred at 30 °C for 2 hours. The reaction was cooled to room temperature and filtered to give N-methyl-6-(4-nitrophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (310 mg, 80% yield) as a solid. LCMS (M+H ⁺ ) m/z: 339.0

[1620] Step 8: Synthesis of 6-(4-aminophenoxy)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1621] A mixture of N-methyl-6-(4-nitrophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (100 mg, 0.3 mmol) and Pd/C (20 mg) in MeOH (10 mL) was stirred at 30 °C under H ₂ for 5 h. The reaction was stirred at 50 °C for 16 hours. The reaction was filtered and concentrated to give 6-(4-aminophenoxy)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (74 mg, 80% yield) as a solid. LCMS (M+H ⁺ ) m/z: 309.0

[1622] Step 9: Synthesis of N-(4-((2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)-4-(trifluoromethyl)picolinesulfonamide

[1623] To a mixture of 4-(trifluoromethyl)picolinic acid (223 mg, 1.0 mmol) in CHCl ₃ (1.0 mL) was added SOCl ₂ (1.0 mL) at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. The reaction was concentrated to give crude 4-(trifluoromethyl)picolinoyl chloride. To a mixture of 6-(4-aminophenoxy)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.2 mmol), DIPEA (78 mg, 0.6 mmol) in DCM (5.0 mL) was added crude 4-(trifluoromethyl)picolinoyl chloride (5 0 mg, 0.24 mmol) was added. The reaction was stirred at 25 °C for 2 hours. The reaction was concentrated and purified by preparative-HPLC (NH ₄ HCO ₃ ) to afford N-(4-((2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)-4-(trifluoromethyl)picolinesulfonamide (23.6 mg, 24% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.86 (s, 1H), 9.04 (d, J = 4.4 Hz, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 8.10-8.09 (m, 1H), 7.93-7.90 (m, 2H), 7 .34 (br, 1H), 7.11–7.08 (m, 2H), 6.88 (br, 1H), 4.09–3.93 (m, 4H), 2.82 (d, J = 4.0 Hz, 3H). LCMS (M+H ⁺ ) m/z: 482.0.

Example 305 N-(3-((6-(2,4- difluorophenoxy )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-yl)amino)phenyl)acrylsulfonamide group (compound 305) manufacturing

[1624] Step 1: Synthesis of ethyl 2-(2,4-difluorophenoxy)acetate

[1625] To a solution of 2,4-difluorophenol (10 g, 76.9 mmol), ethyl 2-chloroacetate (9.4 g, 76.9 mmol) in CH3CN (300 mL) was added K ₂ CO ₃ (12.7 g, 92.3 mmol). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated in vacuo. The residue was diluted in water (200 mL) and extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give ethyl 2-(2,4-difluorophenoxy)acetate (17 g, crude) as a pale yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.33-7.27 (m, 1H), 7.19-7.15 (m, 1H), 7.02-6.97 (m, 1H), 4.86 (s, 2H), 4.20-4.14 (m, 2H), 1.24-1.19 (m, 3H),

[1626] Step 2: Synthesis of 6-(2,4-difluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[1627] K ₂ CO ₃ (25.3 g, 183 mmol) was added to a solution of ethyl 2-(2,4-difluorophenoxy)acetate (18 g, 83.3 mmol), 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (12.7 g, 75 mmol) in NMP (150 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was added dropwise to ice water (1 L). The precipitate obtained was filtered and washed with water (100 mL). The solid was collected and dried to give 6-(2,4-difluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (11 g, 41% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 322.1

[1628] Step 3: Synthesis of 7-chloro-6-(2,4-difluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidine

[1629] A solution of 6-(2,4-difluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (11 g, 34.2 mmol) in POCl ₃ (100 mL) was stirred at 95 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted in water (500 mL) and extracted with DCM (300 mL x 2). The combined organic layers were washed with saturated NaHCO ₃ (500 mL) and concentrated to give the crude which was purified on a silica column (EA/PE = 0% to 30%) to give 7-chloro-6-(2,4-difluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidine (6.5 g, 56% yield) as a yellow solid. LCMS (M + H ⁺ ) m/z: 340.1

[1630] Step 4: Synthesis of 2-((6-(2,4-difluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol

[1631] 2-Aminoethane-1-ol (1.75 g, 28.7 mmol) was added to a solution of 7-chloro-6-(2,4-difluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidine (6.5 g, 19 mmol) in i-PrOH (100 mL). The reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was concentrated to give a crude which was purified on a silica column (EA/PE = 0% to 90%) to give 2-((6-(2,4-difluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (6.0 g, 86% yield) as a yellow solid. LCMS (M + H ⁺ ) m/z: 364.9

[1632] Step 5: Synthesis of 6-(2,4-difluorophenoxy)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[1633] SOCl ₂ (9.8 g, 82.3 mmol) was added to a solution of 2-((6-(2,4-difluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)amino)ethan-1-ol (6.0 g, 16.5 mmol) in CHCl ₃ (100 mL). The reaction mixture was stirred at 65 °C for 3 hours. The mixture was saturated NaHCO ₃ (200 mL) and extracted with DCM (150 mL x 2). The combined organic layers were washed with brine (200 mL) and concentrated to give the crude product which was purified on a silica column (EA/PE = 0% to 90%) to afford 6-(2,4-difluorophenoxy)-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (4.3 g, 75% yield) as a yellow solid. did LCMS (M+ H ⁺ ) m/z: 347.1

[1634] Step 6: Synthesis of 6-(2,4-difluorophenoxy)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine

[1635] A solution of oxone (1.2 g, 1.95 mmol) in water (10 mL) was dissolved in 6-(2,4-difluorophenoxy)-2-(methylthio)-8,9 in THF (10 mL). -dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (270 mg, 0.78 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was saturated NaHCO ₃ (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (30 mL) and concentrated to give 6-(2,4-difluorophenoxy)-2-(methylsulfonyl)-8,9-dihydroimidazo [1',2' :1,6]pyrido[2,3-d]pyrimidine (270 mg, 92% yield) was obtained as a brown solid. LCMS (M + H ⁺ ) m/z: 378.9

[1636] Step 7: Synthesis of 6-(2,4-difluorophenoxy)-N-(3-nitrophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1637] TFA (1.05 g, 9.1 mmol) was diluted with 3-nitroaniline (438 mg, 3.2 mol), 6-(2,4-difluorophenoxy)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (1 g, 2.6 mmol) in DMSO (30 mL). added to the solution. The reaction mixture was stirred at 120 °C for 3 hours. The mixture was saturated NaHCO ₃ (100 mL) and extracted with DCM (60 mL x 3). The combined organic layers were washed with brine (80 mL) and concentrated to give the crude product which was purified by preparative-HPLC (0.1% FA) to give 6-(2,4-difluorophenoxy)-N-(3-nitrophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (650 mg, 56% yield) as brown Obtained as a solid. LCMS (M+H ⁺ ) m/z: 437.1

[1638] Step 8: Synthesis of N1-(6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-2-yl)benzene-1,3-diamine

[1639] Fe powder (767 mg, 13.7 mmol) was added to NH ₄ Cl (441 mg, 8.24 mol), 6-(2,4-difluorophenoxy)-N-(3-nitrophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-2 in EtOH/H ₂ O (2:1) (30 mL). -Amine (600 mg, 1.37 mmol) was added to the mixture. The reaction mixture was stirred at 85 °C for 16 hours. The mixture was filtered and the filtrate was (50 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL) and concentrated to give the crude product which was purified on a silica column (EA/PE=5% to 90%, DCM/MeOH = 9:1) to obtain N1-(6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-2-yl)benzene-1,3-di The amine (210 mg, 38% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 407.0

[1640] Step 9: Synthesis of N-(3-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)acrylsulfonamide formate

[1641] Acryloyl chloride (46.8 mg, 0.52 mmol) was added to N1-(6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)benzene-1,3-diamine (210 mg, 0.52 mmol) in HF/H ₂ O (1:1) (6 mL) ), DIEA (200 mg, 1.55 mmol). The solution was stirred 1 hour at room temperature. The mixture was saturated NaHCO ₃ (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (40 mL), Na ₂ SO ₄ Drying, filtration and concentration gave the crude product, which was purified by preparative-HPLC (0.1% HCOOH) to obtain N-(3-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)acrylsulfonamide formate (43.8 mg, 18.4% yield) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.08 (s, 1H), 9.73 (s, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.51-7.42 (m, 2H), 7.36-7.34 (m, 1 H), 7.28-7.21 (m, 2H), 7.15-7.09 (m, 1H), 6.81 (s, 1H), 6.51-6.44 (m, 1H), 6.27-6.23 (m, 1H), 5.74 (dd, J = 10.0, 2.0 Hz, 1H), 4.20 (t, J = 9.6 Hz, 2H), 4.03 (t, J = 9.6 Hz, 2H). LCMS (M+H ⁺ ) m/z: 461.4.

Example 306 N-(4-((6-(2,4- difluorophenoxy )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-2-yl)amino)phenyl)acrylsulfonamide (Compound 306)

[1642] Step 1: Synthesis of N1-(6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-2-yl)benzene-1,4-diamine

[1643] Benzene-1,4-diamine (106 mg, 0.98 mmol) was added to a solution of 6-(2,4-difluorophenoxy)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (310 mg, 0.82 mmol) in DMSO (3 mL). The reaction mixture was stirred at 120 °C for 2 hours. The mixture was saturated NaHCO ₃ (50 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL) and concentrated to give the crude product which was purified on a silica column (DCM:MeOH = 9:1) to obtain N1-(6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-2-yl)benzene-1,4-diamine (300 mg, 90% aqueous rate) was obtained as a dark brown solid. LCMS (M+H ⁺ ) m/z: 407.1

[1644] Step 2: Synthesis of N-(4-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-2-yl)amino)phenyl)acrylsulfonamide formate

[1645] Acryloyl chloride (60 mg, 0.66 mmol) was added to N1-(6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)benzene-1,4-diamine (270 mg, 0.66 mmol) in THF/H ₂ O(1:1) (20 mL) , to a solution of DIEA (257 mg, 1.99 mmol) at 0 °C. The solution was stirred 1 hour at room temperature. The mixture was quenched with saturated NaHCO ₃ (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give the crude product, which was purified by preparative-HPLC (0.1% HCOOH) to obtain N-(4-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino) Phenyl)acrylsulfonamide formate (5 mg, 1.5% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.05 (s, 1H), 9.67 (s, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 9.2 Hz, 2H), 7.50-7.45 (m, 1H), 7.35-7.32 (m, 1H), 7.14-7.09 (m, 1H), 6.78 (s, 1H), 6.46-6.39 (m, 1H), 6.23 (dd, J = 16.8, 2.0 Hz, 1H), 5.72 (dd, J = 10.0, 2.0 Hz, 1H), 4.12 (t, J = 9.2 Hz, 2H), 4.02 (t, J = 9.2 Hz, 2H). LCMS (M+H ⁺ ) m/z: 461.3.

Example 307:1 -(3-((6-(2,4- difluorophenoxy )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one (compound 307) manufacturing

[1646] Step 1: Synthesis of tert-butyl 3-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate

[1647] tert-butyl 3-aminopyrolidin-1-carboxylate (290 mg, 1.6 mmol) 6- (2,4-defluorophenoxy) -2- (methyl sulfonyl) -2- (methyl sulfonyl) -8,9-dihydo [1 ', 2' 1,6] pyrimidine 500 mg , 1.3 mmol) was added to a solution. The reaction mixture was stirred at 120 °C for 2 hours. water mixture (50 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give tert-butyl 3-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1′,2′:1,6] pyrido[2,3-d] pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate (550 mg, crude) did LCMS (M+H ⁺ ) m/z: 485.1

[1648] Step 2: Synthesis of 6-(2,4-difluorophenoxy)-N-(pyrrolidin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1649] A solution of tert-butyl 3-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate (500 mg, 1.03 mmol) in HCl/dioxane (10 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. Saturate the residue with NaHCO ₃ (20 mL) and extracted with DCM (30 mL x 4). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give 6-(2,4-difluorophenoxy)-N-(pyrrolidin-3-yl)-8,9-dihydroimidazo[1’,2’:1,6]pyrido[2,3-d]pyrimidin-2-amine (330 mg, 83% yield). LCMS (M+H ⁺ ) m/z: 385.2

[1650] Step 3: Synthesis of 1-(3-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one

[1651] Acryloyl chloride (78 mg, 0.85 mmol) was added to 6-(2,4-difluorophenoxy)-N-(pyrrolidin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (330 mg, 0.85 mmol), TEA (260 mg, 2 .57 mmol) was added to the solution. The solution was stirred 1 hour at room temperature. The mixture was saturated NaHCO ₃ (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product which was purified by preparative-HPLC (0.1% NH ₃ .H ₂ O) to give 1-(3-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1’,2’:1,6]pyrido[2,3-d]pyrimidine- Obtained 2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one (59 mg, 15.7% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.15 (s, 1H), 7.66-7.65 (m, 1H), 7.48-7.43 (m, 1H), 7.32-7.26 (m, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.77 (s, 1H), 6.62-6.49 (m, 1H), 6.15-6.09 (m, 1H), 5.68-5.62 (m, 1H), 4.45-4.36 (m, 1H), 4.00-3.94 (m, 4H), 3.76-3.71 (m, 1H), 3.64-3.54 (m, 2H), 3.48-3.41 (m, 1H), 2.10-2.09 (m, 1H), 2.00-1.91 (m, 1H). LCMS (M+H ⁺ ) m/z: 439.3.

Example 308:1 -(3-((6-(2,4- difluorophenoxy )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one (compound 308) manufacturing

[1652] Step 1: Synthesis of tert-butyl 3-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate

[1653] tert-Butyl 3-aminopiperidine-1-carboxylate (140 mg, 0.70 mmol) was added to a solution of 6-(2,4-difluorophenoxy)-2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (220 mg, 0.58 mmol) in DMSO (6 mL) added. The reaction mixture was stirred at 120 °C for 2 hours. water mixture (30 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with brine (50 mL) and dried over Na ₂ SO ₄ , filtered, concentrated to give tert-butyl 3-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (350 mg, crude) LCMS (M+H ⁺ ) m/z: 499.0

[1654] Step 2: Synthesis of 6-(2,4-difluorophenoxy)-N-(piperidin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1655] A solution of tert-butyl 3-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (270 mg, crude) in HCl/dioxane (5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. Saturate the residue with NaHCO ₃ (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL) and concentrated to give crude which was purified by preparative-HPLC (acetonitrile/H ₂ O = 0% to 50%) to yield 6-(2,4-difluorophenoxy)-N-(piperidin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine- 2-amine was obtained (120 mg, 56% yield). LCMS (M+H+) m/z: 399.2

[1656] Step 3: Synthesis of 1-(3-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one

[1657] Acryloyl chloride (27 mg, 0.30 mmol) was added to 6-(2,4-difluorophenoxy)-N-(piperidin-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (120 mg, 0.30 mmol), TEA (91 mg, 0.30 mmol) in DCM (5 mL). 90 mmol) was added to the solution. The solution was stirred 1 hour at room temperature. The mixture was saturated NaHCO ₃ (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (50 mL) and concentrated to give the crude product which was purified by preparative-HPLC (0.1% ammonia) to obtain 1-(3-((6-(2,4-difluorophenoxy)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)prop-2-ene Obtained -1-one (16.53 mg, 12.2% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.13 (s, 1H), 7.48-7.26 (m, 3H), 7.09 (t, J = 7.6 Hz, 1H), 6.84-6.77 (m, 2H), 6.10-6.06 (m, 1H), 5.67-5.61 (m, 1H), 4.17-4.13 (m, 1H), 3.98-3.47 (m, 6H), 3.06-2.81 (m, 1H), 2.69-2.52 (m, 1H), 1.94-1.92 (m, 1H), 1.79-1.76 (m, 1H), 1.64-1.53 (m, 1H), 1.42-1.39 (m, 1H). LCMS (M+H ⁺ ) m/z: 453.0.

Example 309 N- methyl -6-(2- methyl -4-((4- Phenylphthalazine Preparation of -1-yl) amino) phenyl) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine

[1658] Step 1: Synthesis of 1-chloro-4-phenylphthalazine

[1659] Pd(dppf)Cl 2 to a solution of 1,4-dichlorophthalazine (652 mg, 3.280 mmol), phenylboronic acid (200 mg, 1.640 mmol) and Na ₂ CO ₃ (521 mg, 4.920 mmol) in _dioxane (30 mL) and H ₂ O (6 mL) (60 mg, 0.082 mmol) was added. The reaction mixture was stirred at 100 °C under N ₂ for 1 hour. The crude product was purified by flash chromatography to give 1-chloro-4-phenylphthalazine (160 mg, 20.2% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 241.1.

[1660] Step 2: Synthesis of N-methyl-6-(2-methyl-4-((4-phenylphthalazin-1-yl)amino)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1661] To a solution of 1-chloro-4-phenylphthalazine (190 mg, 0.623 mmol) and 6-(4-amino-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (150 mg, 0.623 mmol) in i-PrOH (6 mL) in HCl/dioxy Acid (6 drops) was added. The reaction mixture was stirred at 100 °C under N ₂ for 3 hours. The resulting solution was extracted with EA (20 mL x 3) and concentrated. The crude product was purified by preparative-TLC (DCM: MeOH=30:1) and preparative-HPLC (0.1%/TFA/CH ₃ CN/H ₂ O) to obtain N-methyl-6-(2-methyl-4-((4-phenylphthalazin-1-yl)amino)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-2- The amine (262.81 mg, 82.6% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.75 (br s, 1H), 8.89 (s, 1H), 8.85 (d, J = 8.4 Hz, 1H), 8.50 (q, J = 4.8 Hz, 1H), 8.22 (t, J = 7.2 Hz, 1H), 8.12-8.08 (m, 2H), 8.00 (d, J =8.0 Hz, 1H), 7.90 (s, 1H), 7.89 (d, J = 8.4 Hz 1H), 7.74-7.72 (m, 2H) 7.66-7.64 (m, 3H), 7.35 (d, J = 8.4 Hz, 1H), 4.69-4.56 (m, 2H), 4.07-4.02 (m, 2H), 2.97 (d, J = 4.8 Hz, 3H), 2.28 (s, 3H). LCMS (M+H+) m/z: 511.0.

Example 310: N- methyl -6-(2- methyl -4-((4-(4- methylthiophene -2 days) phthalazine -1-yl)amino)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (compound 310) manufacturing

[1662] Step 1: Synthesis of 1-chloro-4- (4-methylthiophen-2-yl) phthalazine

[1663] 1,4-dichlorophthalazine (800 mg, 4.019 mmol), 4,4,5,5-tetramethyl-2-(4-methylthiophen-2-yl)-1,3,2-dioxaborolane (300 mg, 2.112 mmol) and Na ₂ CO ₃ (672 mg, 6.33 mmol) in dioxane (30 mL) and H ₂ O (6 mL) 6 mmol) of Pd(dppf)Cl ₂ (77 mg, 0.105 mmol) was added. The reaction mixture was stirred at 100 °C under N ₂ for 2 h. The crude product was purified by flash chromatography to give 1-chloro-4-(4-methylthiophen-2-yl)phthalazine (375 mg, 1.438 mmol, 35.7% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 261.1.

[1664] Step 2: Synthesis of N-methyl-6-(2-methyl-4-((4-(4-methylthiophen-2-yl)phthalazin-1-yl)amino)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1665] 1-chloro-4- (4-methylthiophen-2-yl) phthalazine (100 mg, 0.326 mmol) and 6- (4-amino-2-methylphenyl) -N-methyl-8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-2-amine (127 mg, 0.489 mmol) was added TFA (1 drop). The reaction mixture was stirred at 100° C. under N ₂ for 3 hours. The resulting solution was extracted with EA (20 mL x 3) and concentrated. The crude product was purified by preparative-TLC (DCM: MeOH=30:1) and preparative-HPLC (0.1%/TFA/CH ₃ CN/H ₂ O) to obtain N-methyl-6-(2-methyl-4-((4-(4-methylthiophen-2-yl)phthalazin-1-yl)amino)phenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2 ,3-d]pyrimidin-2-amine TFA salt (64.5 mg, 30.7% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.68 (d, J = 7.6 Hz , 1H), 8.44-8.42 (m, 2H), 8.14 (s, 1H), 8.10-8.02 (m, 2H), 7.89-7.87 (m, 2H), 7.53 (s, 1H), 7.33 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.29-4.13 (m, 2H), 3.98-3.94 (m, 2H), 2.89 (s, 3H), 2.34 (s, 3H), 2.27 (s, 3H). LCMS (M+H ⁺ ) m/z: 531.1.

Example 311:1 - cyclopropyl -3-(3- Fluoro -4-((2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)oxy)phenyl)urea (compound 311) manufacturing

[1666] Step 1: Synthesis of phenyl (3-fluoro-4-((2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d] pyrimidin-6-yl)oxy)phenyl)carbamate

[1667 _] Phenyl _{carbonochloridate} (249 mg, 1.59 mmol) was added. The resulting mixture was stirred at 0°C for 3 hours. The reaction mixture was added with water (100 mL) and filtered. The collected cakes were purified by column chromatography (DCM: MeOH = 15: 1, +0.1% TEA) on the silica gel, and phenyl (3-fluoro-4- (2- (2- (methylamino) -8,9-dihydro) already dazza [1 ', 2': 1,6] pyramidine-6-yxy) Cabamate (50 mg, 9.1% yield) was obtained as a gray -white solid. LCMS (M+H ⁺ ) m/z: 447.2

[1668] Step 2: Synthesis of 1-cyclopropyl-3-(3-fluoro-4-((2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)urea

[1669] DMF (1.5.0 mL) of the sealed test tube among the phenyl (3-fluoro-4-(2- (methylamino) -8,9-dihydroida [1 ', 2': 1,6] pyrimidine-6-yl) Cabamate (50 mg, 0.112 mmol) and cyclopropania Mixture of civil (25 mg, 0.448 mmol). The resulting mixture was stirred at 40°C for 4.0 hours. 반응 혼합물을 농축하여 시클로프로판아민을 제거하고 분취형-HPLC (0.1%NH ₃ -H ₂ O)로 정제하여 -시클로프로필-3-(3-플루오로-4-((2-(메틸아미노)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-6-일)옥시)페닐)우레아 (16.0 mg, 34.9% 수율)를 회백색 고체로서 수득하였다 ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.54 (s, 1H), 8.10 (s, 1H), 7.61 (dd, J = 10.0, 2.4 Hz, 1H), 7.21-7.18 (m, 1H), 7.18-7.13 (m, 2H), 6.53 (s, 1H), 6.47 (d, J = 2.4 Hz, 1H), 4.00-3.96 (m, 4H), 2.79 (d, J = 4.4 Hz, 3H), 2.56-2.52 (m, 1H), 0.66-0.62 (m, 2H), 0.43-0.39 (m, 2H). LCMS (M+H ⁺ ) m/z: 410.1.

Example 312:1 - cyclopropyl -3-(4-((2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)oxy)phenyl)urea (compound 312) manufacturing

[1670] Step 1: Synthesis of 1-cyclopropyl-3-(4-((2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)urea

[1671] A mixture of 6-(4-aminophenoxy)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (30 mg, 0.1 mmol), isocyanatocyclopropane (27 mg, 0.12 mmol), DIPEA (40 mg, 0.3 mmol) in DCM (3 mL) at 20°C was stirred for 30 minutes. The reaction was purified by preparative-HPLC (0.1%NH ₄ HCO ₃ ) to afford 20.5 mg of 1-cyclopropyl-3-(4-((2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)urea as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.34 (s, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 7.40 (d, J = 9.2 Hz, 2H), 7.26 (br, 1H), 6.96 (d, J = 9.2 Hz, 2H), 6.66 (br, 1H), 6.40 (d, J = 2.4 Hz, 1H), 4.05-3.92 (m, 4H), 2.80 (d, J = 4.0 Hz, 3H), 2.54-2.53 (m, 1H), 0.65-0.60 (m, 2H), 0.41-0.37 (m, 2H). LCMS (M+H ⁺ ) m/z: 392.2.

Example 313: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)urea (compound 313) manufacturing

[1672] Step 1: Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)urea

[1673] To a mixture of 6-(4-aminophenoxy)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.2 mmol) in DCM (3 mL), 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (53 mg, 0.24 mmol) and DIPEA (77 mg, 0.6 mmol) was added at room temperature. The reaction mixture was stirred at 20 °C for 30 minutes. The reaction was purified by preparative-HPLC to afford 28.8 mg of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)urea as a formic acid salt yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.46 (s, 1H), 9.15 (s, 1H), 8.19 (s, 2H), 8.11 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 9.2, 2.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.41 (br, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.89 (br, 1H), 4.14-3.95 (m, 4H), 2.81 (s, 3H). LCMS (M+H ⁺ ) m/z: 529.8.

Example 314: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)urea (compound 314) manufacturing

[1674] Step 1: Synthesis of tert-butyl 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)urea

[1675] 1-chloro-4-isocyanato-2- (trifluoromethyl) benzene (77 mg, 0.35 mmol) was added. The resulting mixture was added at room temperature for 16 hours under N ₂ . The reaction mixture was quenched with H ₂ O (20 mL) and extracted with DCM (20.0 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH=10/1) to obtain 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((2-(methylthio)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)urea. (110 mg, 67% yield) Obtained as a yellow oil. LCMS (M+H ⁺ ) m/z: 565.1.

[1676] Step 2: Synthesis of tert-butyl 6-(3-(2,4-dichlorobenzoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[1677] To a solution of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)urea (90 mg, 0.16 mmol) in DCM (5.0 mL), m-CPBA ( 64 mg, 0.32 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated to give tert-butyl 6-(3-(2,4-dichlorobenzoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (120 mg, crude) as an off-white solid. LCMS (M+H ⁺ ) m/z: 581.2.

[1678] Step 3: Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)urea

[1679] To a mixture of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((2-(methylsulfinyl)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)urea (120 mg, 0.21 mmol) in THF (2.0 mL) MeNH ₂ (1 mL, 1M in THF) was added. The mixture was concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH=10/1) to give the crude product which was further purified by preparative-HPLC (0.1% ammonia) to give 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine- Obtained 6-yl)oxy)phenyl)urea (17.7 mg, 15.7% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.24 (s, 1H), 9.08 (s, 1H), 8.12-8.10 (m, 2H), 7.69-7.61 (m, 3H), 7.23-7.18 (m, 3H), 6.64 (s, 1H), 4.00- 3.96 (m, 4H), 2.81 (d, J = 4.4 Hz, 3H). LCMS (M+H ⁺ ) m/z: 548.2.

Example 315:1 - cyclopropyl -3-(2- Fluoro -4- methyl -5-(2-( methylamino )-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (Compound 315)

[1680] The preparation of 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 139.

[1681] Step 1: Synthesis of phenyl (2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate

[1682] To a solution of 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (80 mg, 0.247 mmol) in pyridine (2 mL) was added phenyl carbonochloridate (386 mg, 2.469 mmol). The reaction mixture was stirred at 50 °C for 16 hours. Concentrated in vacuo to give phenyl (2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (80 mg, crude) which was used directly in the next step.

[1683] Step 2: Synthesis of 1-cyclopropyl-3-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea

[1684] To a solution of phenyl (2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (80 mg, 0.180 mmol) in pyridine (3 mL) was added cyclopropylamine (31 mg, 0.541 mmol). The reaction mixture was stirred at room temperature for 16 hours. LCMS results indicated that the reaction performed well. The resulting mixture was purified by preparative-HPLC (0.1% TFA) to afford 1-cyclopropyl-3-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (6.1 mg, 13.2%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.77 (s, 1H), 8.00 (s, 1 H), 7.89 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 12.0 Hz, 1H), 4.77 (t, J = 10.0 Hz, 2H), 4.12 (t, J = 10.0 Hz, 2H), 3.07 (s, 3H), 2.59–2.57 (m, 1H), 2.21 (s, 3H), 0.75–0.73 (m, 2H), 0.52–0.48 (m, 2H). LCMS (M+H ⁺ ) m/z: 408.1.

Example 316: 1- (2-fluoro-4-methyl-5- (2- (methylamino) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-6-yl) phenyl) -3- (3,3,3-trifluoropropyl) urea (compound 316) manufacturing

[1685] Step 1: Synthesis of 1-(5-bromo-2-fluoro-4-methylphenyl)-3-(3,3,3-trifluoropropyl)urea

[1686] To a solution of 4,4,4-trifluorobutanoic acid (540 mg, 3.8 mmol) in THF (8 mL) was added DPPA (1.05 g, 3.8 mmol) and DIEA (980 mg, 7.6 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. Then 5-bromo-2-fluoro-4-methylaniline (775 mg, 3.8 mmol) was added and the reaction mixture was stirred at 80° C. for 4 hours. LCMS showed the reaction to be complete. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mLx 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated to give a white solid which was purified by chromatography column (PE:EA=1:1) to give 1-(5-bromo-2-fluoro-4-methylphenyl)-3-(3,3,3-trifluoropropyl)urea (750 mg, 58% yield). LCMS (M+H ⁺ ) m/z: 342.8

[1687] Step 2: Synthesis of 1-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3,3,3-trifluoropropyl)urea

[1688] Pin2B2 (557 mg, 2.19 mmol), KOAc (358 mg, 4.38 mmol) and Pd(dppf)Cl ₂ (153 mg, 0.2 2 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 85 °C for 2 hours. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL), extracted with EA (10 mL*3), the combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by chromatography column (PE:EA=2:1) to give 1-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol) Obtained lan-2-yl)phenyl)-3-(3,3,3-trifluoropropyl)urea (510 mg, 60% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 391.2

[1689] Step 3: Synthesis of 1-(2-fluoro-4-methyl-5-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3,3-trifluoropropyl)urea

[1690] 디옥산 (4 mL) 및 H ₂ O (1 mL) 중 1-(2-플루오로-4-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-3-(3,3,3-트리플루오로프로필)우레아 (200 mg, 0.51 mmol)의 용액에 6-브로모-2-(메틸티오)-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘 (151 mg, 0.51 mmol), K ₂ CO ₃ (142 mg, 1.02 mmol) 및 Pd(dppf)Cl ₂ (37 mg, 0.05 mmol)를 질소 분위기 하에 첨가하였다. The mixture was stirred at 80 °C for 3 hours. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by chromatography column (PE:EA=1:2) to yield 1-(2-fluoro-4-methyl-5-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl) -3-(3,3,3-trifluoropropyl)urea (80 mg, 33% yield) was obtained as a yellow solid. LCMS (M+H+) m/z: 480.9

[1691] Step 4: Synthesis of 1-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3,3-trifluoropropyl)urea

[1692] 6-Bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrido in DCM (5 mL) To a solution of midine (80 mg, 0.17 mmol) was added m-CPBA (59 mg, 0.34 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. LCMS showed the reaction to be complete. The reaction mixture was concentrated to give a yellow solid. The crude solid in THF (3 mL) was added to methylamine in THF (1 mL, 2 mmol). The mixture was stirred at room temperature for 1 hour. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by pre-HPLC to give 1-(2-fluoro-4-methyl -5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3 -(3,3,3-trifluoropropyl)urea (38.2 mg) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.41 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.52-7.43 (m, 1H), 7.16–7.12 (m, 1H), 7.07 (d, J = 12.4 Hz, 1H), 6.73 (t, J = 6.0 Hz, 1H), 4.10–3.94 (m, 2H), 3.90 ( t, J = 9.2 Hz, 2H), 3.32–3.28 (m, 2H), 2.84 (s, 3H), 2.42–2.38 (m, 2H), 2.13 (s, 3H). LCMS (M+H ⁺ ) m/z: 464.0.

Example 317:1 -(3,3- dimethyl butyl )-3-(2- Fluoro -4- methyl -5-(2-( methylamino Preparation of )-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (Compound 317)

[1693] Step 1: Synthesis of 1-(5-bromo-2-fluoro-4-methylphenyl)-3-(3,3-dimethylbutyl)urea

[1694] To a solution of 4,4-dimethylpentanoic acid (500 mg, 3.8 mmol) in THF (8 mL) was added DPPA (1.05 g, 3.8 mmol) and DIEA (980 mg, 7.6 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. Then 5-bromo-2-fluoro-4-methylaniline (775 mg, 3.8 mmol) was added and the reaction mixture was stirred at 80° C. for 4 hours. LCMS showed the reaction to be complete. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated to give a white solid which was purified by chromatography column (PE:EA=1:1) to give 1-(5-bromo-2-fluoro-4-methylphenyl)-3-(3,3-dimethylbutyl)urea (220 mg, 30% yield). LCMS (M+H ⁺ ) m/z: 333.0

[1695] Step 2: 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-di Synthesis of oxabololan-2-yl)phenyl)urea

[1696] Pin2B2 (201 mg, 0.79 mmol), KOAc (129 mg, 1.32 mmol) and Pd(dppf)Cl2 (51 mg, 0.07 mmol) were added to a solution of 1-(5-bromo-2-fluoro-4-methylphenyl)-3-(3,3-dimethylbutyl)urea (220 mg, 0.66 mmol) in dioxane (5 mL) under a nitrogen atmosphere. added under. The mixture was stirred at 85 °C for 2 hours. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by chromatography column (PE:EA=2:1) to obtain 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (80 mg) , 32% yield) as a white solid. LCMS (M+H ⁺ ) m/z: 379.0

[1697] Step 3: Synthesis of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea

[1698] 6-Bromo-N-methyl-8,9-dihydroimidazo[1 ',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (58 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol) and Pd(dppf)Cl2 (15 mg, 0.02 mmol) were added under a nitrogen atmosphere. The mixture was stirred at 80 °C for 3 hours. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by prep-HPLC to give 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6 -yl)phenyl)urea (10.1 mg) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.28 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.53-7.48 (m, 1H), 7.22-7.15 (m, 1H), 7.06 (d, J = 12.0 Hz, 1H), 6.46 (t, J = 5.2 Hz, 1H), 4.13-4.00 (m, 2H), 3.90 (t, J = 10.0 Hz, 2H), 3.10-3.04 (m, 2H), 2.85 (s, 3H), 2.12 (s, 3H), 1.38-1.27 (m, 2H), 0.88 (s, 9H). LCMS (M+H ⁺ ) m/z: 452.0.

Example 318:1 -(3,3- dimethyl butyl )-3-(2- Fluoro -4- methyl -5-((2-( methylamino )-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)amino)phenyl)urea (compound 318) manufacturing

[1699] Step 1: Synthesis of tert-butyl (6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)(methyl)carbamate

[1700] A mixture of 6-bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (500 mg, 1.79 mmol), (Boc) ₂ O (1.54 g, 7.14 mmol) and DMAP (22 mg, 0.179 mmol) in THF (20.0 mL) was heated to 55 °C. was stirred for 16 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH=20:1) to afford tert-butyl (6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)(methyl) carbamate (587 mg, 86.5% yield) as a brown oil. LCMS (M+H ⁺ ) m/z: 380.0 and 382.0.

[1701] Step 2: Synthesis of tert-butyl (6-((4-fluoro-2-methyl-5-nitrophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)(methyl)carbamate

[1702] tert-butyl (6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)(methyl)carbamate (200 mg, 0.53 mmol) and 4-fluoro-2-methyl-5-nitroaniline (134 mg, 0.79 mmol) in toluene (5.0 mL), Pd(O Ac) ₂ (24 mg, 0.11 mmol), x-phos (125 mg, 0.26 mmol) and t-BuOK (177 mg, 1.58 mmol) was stirred at 130° C. for 16 h under N ₂ . The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (PE/EA=2/1) followed by preparative-HPLC (ACN%=46%, 0.1%HCl) to yield crude tert-butyl (6-((4-fluoro-2-methyl-5-nitrophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl) (Methyl)carbamate (70 mg, 28.3% yield) was obtained as a yellow solid. LCMS (M+H ⁺ ) m/z: 470.3

[1703] Step 3: Synthesis of tert-butyl (6-((5-amino-4-fluoro-2-methylphenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)(methyl)carbamate

[1704] tert-butyl (6-((4 _- fluoro-2-methyl-5-nitrophenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)(methyl)carbamate (70 mg, 0.15 mmol) and NH ₄ Cl (81 mg, 1.5 mmol) was added Fe (84 mg, 1.5 mmol). The mixture was stirred at 80° C. for 3.0 h under N ₂ then diluted with water (20.0 mL) and extracted with EA (30 mL x3). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford tert-butyl (6-((5-amino-4-fluoro-2-methylphenyl)amino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-yl)(methyl)carbamate (50 mg, 76.3% yield) as a brown solid. LCMS (M+H ⁺ ) m/z: 440.3.

[1705] Step 4: Synthesis of tert-butyl (6-((5-(3-(3,3-dimethylbutyl)ureido)-4-fluoro-2-methylphenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)(methyl)carbamate

[1706] tert-butyl (6-((5-amino-4-fluoro-2-methylphenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)(methyl)carbamate (15 mg, 0.034 mmol) and Et ₃ N (10.3 mg, 0.102 mmol) in THF (1.5 mL) Triphosgene (5.0 mg, 0.017 mmol) was added to the mixture and the mixture was stirred at room temperature for 1.0 h. A solution of 3,3-dimethylbutan-1-amine (7.0 mg, 0.068 mmol) in THF (0.5 mL) was added dropwise. The resulting mixture was stirred at room temperature for 5.0 h under N ₂ . After reaction completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL x3). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to yield crude tert-butyl (6-((5-(3-(3,3-dimethylbutyl)ureido)-4-fluoro-2-methylphenyl)amino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)(methyl)carbamate (15 mg, 78.9% yield) as a brown oil. LCMS (M-Boc+H ⁺ ) m/z: 467.4.

[1707] Step 5: Synthesis of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-((2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)amino)phenyl)urea hydrogen chloride

[1708] Tert-butyl (6- ((5- (3,3-dimethyl butyl) -4-fluoro-2-methylphenyl) amino) -8,9-dihydro dazzo [1 ', 2': 1,6] pyrimidin-2-yl) (methyl) TFA (1.0 mL) was added to the solution. The resulting mixture was stirred at room temperature for 1.5 hours and concentrated. The residue was purified by preparative-HPLC (0.1%NH ₃ H ₂ O) then preparative-HPLC (0.1%HCl) to obtain 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-((2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)amino)phenyl) Urea hydrogen chloride (1.87 mg, 15.1% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.73 (s, 1H), 7.72 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 11.6 Hz, 1H), 4.78-4.76 (m, 2H), 4.25 (t, J = 10.0 Hz, 2H), 3.22–3.17 (m, 2H), 3.06 (s, 3H), 2.20 (s, 3H), 1.45–1.41 (m, 2H), 0.94 (s, 9H). LCMS (M+H ⁺ ) m/z: 467.3.

Example 319: preparation of 1-(4-chloro-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)urea

[1709] Step 1: Synthesis of 1-(4-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)urea

[1710] To a solution of 1-amino-3,3-dimethylbutan-2-ol (51 mg, 0.44 mmol) and TEA (133 mg, 1.32 mmol) in THF (2 mL) was added triphosgene (32 mg, 0.11 mmol). The solution was stirred at room temperature under N2 for 1 hour. The reaction solution was then added to a solution of 4-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (60 mg, 0.22 mmol) in THF (2 mL). The mixture was stirred at room temperature under N2 for 1 hour. The mixture was filtered. The filtrate was diluted with DCM/MeOH (10/1, 100 mL) and washed with water (20 mL). The organic phase was concentrated to give 1-(4-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)urea (92 mg crude) as a yellow oil. LCMS (M+H ⁺ ) m/z: 333.1 and 415.3.

[1711] Step 2: Synthesis of 1-(4-chloro-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)urea hydrochloride

[1712] 디옥산 (6 mL) 및 물 (1.5 mL) 중 1-(4-클로로-2-플루오로-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-3-(2-히드록시-3,3-디메틸부틸)우레아 [1713] (90 mg 미정제, 0.22 mmol), 6-브로모-N-메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (62 mg, 0.22 mmol), Cs ₂ CO ₃ (215 mg, 0.66 mmol) 및 Pd(dppf)Cl ₂ (16 mg, 0.022 mmol)의 혼합물을 100℃에서 N ₂ 하에 1시간 교반하였다. The reaction mixture was cooled to room temperature and purified by flash chromatography to give 40 mg of crude product which was purified by preparative-HPLC (0.1%/HCl/CH ₃ CN/H ₂ O) to give 1-(4-chloro-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3- (2-hydroxy-3,3-dimethylbutyl)urea hydrochloride (14.9 mg, 13% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.88 (s, 2H), 8.59-8.46 (m, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.17 (s, 1H), 7.64 (d, J = 11.2 Hz, 1H), 6.94 (s, 1H), 4.69-4.53 (m, 2H), 4.12-3.97 (m, 2H), 3.46-3.43 (m, 1H), 3.08 (d, J = 8.4 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H), 2.51-2.49 (m, 1H), 0.88 (s, 9H). LCMS (M+H ⁺ ) m/z: 488.2.

Example 320: 1-(6-(5-amino-2-chloro-4-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-3-(2-hydroxy-3,3-dimethylbutyl)-1-methylurea (compound 320) manufacturing

[1714] Step 1: Synthesis of 1-(4-chloro-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)urea

[1715] Triphosgene (18.4 mg, 0.062mmol, 0.4eq) to a mixture of 6-(5-amino-2-chloro-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.16 mmol, 1.0 eq) in THF (10 mL) ) and TEA (47 mg, 0.468 mmol, 3.0 eq) were added. The mixture was stirred at room temperature under N2 for 1 hour. Then 1-amino-3,3-dimethylbutan-2-ol (36 mg, 0.31 mmol, 2.0 eq) was added. The mixture was stirred at room temperature under N2 for 2 hours. The resulting mixture was purified by preparative-HPLC (0.1% TFA) to afford 1-(4-chloro-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)urea (14.3 mg, 18.4%) as a yellow solid. obtained. ¹ H NMR (400 MHz, CD ₃ OD): δ 9.14 (s, 1H), 8.26 (s, 1H), 7.28 (d, J = 10.8 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 4.94-4.85 (m, 2H), 4.26-4.20 (m, 2H), 3.82 (dd, J = 13.2, 2.4 Hz, 1H), 3.64 (s, 3H), 3.40 (dd, J = 10.0, 2.4 Hz, 1H), 3.15–3.09 (m, 1H), 0.98 (s, 9H). LCMS (M+H ⁺ ) m/z: 488.0.

Example 321: 1-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)urea (compound 321) manufacturing

[1716] Step 1: Synthesis of 1-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)urea

[1717] 1-amino-3,3-dimethylbutan-2-ol (40 mg, 0.34 mmol, 2.0 eq) and TEA in THF (15 mL) (33 mg, 0.0.51 mmol, 3.0 eq) was added triphosgene (20 mg, 0.07 mmol, 0.4 eq). The mixture was stirred at 0 °C for 1 hour. After 1 hour, 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.17 mmol, 1.0 eq) was added to the solution. The mixture was stirred at room temperature for 16 hours. LCMS results indicated that the reaction performed well. The resulting mixture was purified by preparative-HPLC (0.1% HCl) to obtain 1-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)urea. (4.7 mg, 5% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.87 (s, 1H), 8.05 (s, 1H), 7.96-7.63 (m, 1H), 7.19 (d, J = 12.0 Hz, 1H), 4.79-4.76 (m, 2H), 4.17 (t, J = 10.0 Hz, 2H), 3.61 (dd, J = 13.6, 2.4 Hz, 1H), 3.32-3.28 (m, 1H), 3.12 (s, 3H), 2.98-2.92 (m, 1H), 2.23 (s, 3H), 0.96 (s, 9H). LCMS (M+H ⁺ ) m/z: 468.1.

Example 322: 1-(6-(5-amino-2-bromo-4-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-3-(2-hydroxy-3,3-dimethylbutyl)-1-methylurea (compound 322) manufacturing

[1718] Step 1: Synthesis of 3,3-dimethyl-1-nitrobutan-2-ol

[1719] To a solution of pivalaldehyde (0.5 g, 5.8 mmol) in toluene (10 mL) was added MeNO ₂ (3 mL) dropwise at -60 °C. After 30 min, n-BuOH (0.1 mL) was added. The mixture was stirred at room temperature for 2 hours. TLC results showed a new point. The crude was diluted with EA (20 mL) and H ₂ O (20 mL). The organic layer was concentrated to give crude 3,3-dimethyl-1-nitrobutan-2-ol (850 mg, 99% yield).

[1720] Step 2: Synthesis of 1-amino-3,3-dimethylbutan-2-ol

[1721] To a solution of 3,3-dimethyl-1-nitrobutan-2-ol (300 mg, 4.4 mmol, 1.0 eq) in MeOH (10 mL) was added Pd/C (30 mg, 10%). The reaction mixture was stirred at 20° C. under H2 for 12 hours. Filtration and concentration gave the crude product 1-amino-3,3-dimethylbutan-2-ol (280 mg, 100%) as an oil.

[1722] Step 3: Synthesis of 1-(6-(5-amino-2-bromo-4-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-3-(2-hydroxy-3,3-dimethylbutyl)-1-methylurea

[1723] 6-(5-amino-2-bromo-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.11 mmol, 1.0 eq) and TEA in THF (15 mL) (33 mg, 0.33 mmol, 3.0 eq) was added triphosgene (15 mg, 0.05 mmol, 0.4 eq). The mixture was stirred at 0 °C for 1 hour. After 1 hour, 1-amino-3,3-dimethylbutan-2-ol was added to the solution. The mixture was stirred at room temperature for 16 hours. LCMS results indicated that the reaction performed well. The obtained mixture was purified by preparative-HPLC (0.1% HCl) to obtain 1-(6-(5-amino-2-bromo-4-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-3-(2-hydroxy-3,3-dimethylbutyl)-1-methylurea (3.1 mg, 4.5% yield) as yellow Obtained as a solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 9.16 (s, 1H), 8.27 (s, 1H), 7.50 (d, J = 10.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 5.04-4.96 (m, 2H), 4.24 (t, J = 9.2 Hz, 2H), 3.82 (dd, J = 13.6, 2.0 Hz, 1H), 3.65 (s, 3H), 3.40 (dd, J = 10.0, 2.0 Hz, 1H), 3.13 (dd, J = 13.6, 2.0 Hz, 1H), 0.98 (s, 9H). LCMS (M+H ⁺ ) m/z: 532.0.

Example 323:1 -(4- Bromo -2- Fluoro -5-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3-dimethylbutyl)urea (compound 323) manufacturing

[1724] Step 1: Synthesis of 1-(4-bromo-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3-dimethylbutyl)urea

[1725] To a mixture of 4,4-dimethylpentanoic acid (50 mg, 0.23 mmol) and TEA (70 mg, 0.69 mmol) in toluene (10 mL) was added DPPA (95 mg, 0.35 mmol) and the mixture was stirred at 25 °C for 1 hour. A mixture of 6-(5-amino-2-bromo-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.15 mmol) in toluene (5 mL) was added to the solution. The mixture was stirred at 110° C. under N ₂ for 12 h in a sealed test tube. LCMS results indicated that the reaction performed well. Concentration and the residue was purified by prep-HPLC (0.1% HCl) to afford 1-(4-bromo-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3-dimethylbutyl)urea (1.5 mg, 4% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.87 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.09 (s, 1H), 7.62 (d, J = 10.4 Hz, 1H), 4.76-4.73 (m, 2H), 4.19-4.14 (m, 2H), 3.27-3.15 (m, 2H), 3.10 (s, 3H), 1.48-1.44 (m, 2H), 1.03 (s, 9H). LCMS (M+H ⁺ ) m/z: 516.1.

Example 324:1 -(4- Chloro -2- Fluoro -5-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3-dimethylbutyl)urea (compound 324) manufacturing

[1726] Step 1: Synthesis of 1-(4-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3,3-dimethylbutyl)urea

[1727] To a solution of 4-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (70 mg, 0.26 mmol) and TEA (79 mg, 0.78 mmol) in THF (6 mL) was added triphosgene (38 mg, 0.13 mmol). The solution was stirred at room temperature under N2 for 1 hour. The reaction solution was then added to a solution of 3,3-dimethylbutan-1-amine (26 mg, 0.26 mmol) in THF (2 mL). The mixture was stirred at room temperature under N2 for 1 hour. The mixture was filtered. The filtrate was diluted with EA (60 mL) and washed with water. The organic phase was concentrated to give a mixture of 1-(4-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3,3-dimethylbutyl)urea (103 mg crude, 100% yield) as a yellow oil. LCMS (M+H+) m/z: 399.4.

[1728] Step 2: Synthesis of 1-(4-chloro-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3-dimethylbutyl)urea hydrochloride

[1729] 1-(4-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3,3-dimethylbutyl)urea (103 mg crude, 0.26 mmol) in dioxane (6 mL) and water (1.5 mL), 6-bromo-N-methyl-8,9-dihydroimidazo [1 A mixture of ',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (73 mg, 0.26 mmol), Cs2CO3 (253 mg, 0.78 mmol) and Pd(dppf)Cl2 (19 mg, 0.026 mmol) was stirred at 100 °C under N2 for 5 h. The reaction mixture was cooled to room temperature and diluted with EA (50 mL) and water (20 mL). The organic phase was concentrated and purified by preparative-TLC (DCM/MeOH = 10/1) and preparative-HPLC (0.1%/HCl/CH3CN/H2O) to obtain 1-(4-chloro-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3 -Dimethylbutyl)urea hydrochloride (14.45 mg, 10.9% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.89 (s, 1H), 8.70 (s, 1H), 8.63-8.45 (m, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 7.66 (d, J = 10.8 Hz, 1H), 6.80 (s, 1H), 4.71-4.60 (m, 2H), 4.06-4.00 (m, 2H), 3.12-3.08 (m, 2H), 2.96 (d, J = 4.8 Hz, 3H), 1.37-1.33 (m, 2H), 0.90 (s, 9H). LCMS (M+H) ⁺ m/z: 472.1.

Example 325:1 -(6-(5-amino-2- Chloro -4- fluorophenyls )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-2-yl)-3-(3,3-dimethylbutyl)-1-methylurea (compound 325) manufacturing

[1730] Step 1: Synthesis of 1-(6-(5-amino-2-chloro-4-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-3-(3,3-dimethylbutyl)-1-methylurea hydrogen chloride

[1731] To a mixture of 6-(5-amino-2-chloro-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (53 mg, 0.14 mmol) in THF (8 mL) was added triphosgene (17 mg, 0.056 mmol). The mixture was stirred at room temperature under N2 for 1 hour. Then a solution of 3,3-dimethylbutan-1-amine (10 mg, 0.098 mmol) and TEA (113 mg, 1.12 mmol) was added. The mixture was stirred at room temperature under N2 for 16 hours and concentrated. The residue was purified by preparative-HPLC (0.1%/HCl/CHCN/H2O) to give 1-(6-(5-amino-2-chloro-4-fluorophenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)-3-(3,3-dimethylbutyl)-1-methylurea hydrogen chloride (2.9 mg, 4% aqueous solution). rate) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.55 (s, 1H), 9.57 (t, J = 5.2 Hz, 1H), 9.21 (s, 1H), 8.38 (s, 1H), 7.42 (d, J = 11.2 Hz, 1H), 6.85 (d, J = 9.2 Hz, 1H), 4.74–4.71 (m, 2H), 4.17–4.12 (m, 2H), 3.49 (s, 3H), 3.23–3.18 (m, 2H), 1.52–1.48 (m, 2H), 0.95 (s, 9H). LCMS (M+H ⁺ ) m/z: 472.1.

Example 326:1 -(4- Bromo -2- Fluoro -5-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)-3-phenylurea (compound 326) manufacturing

[1732] Step 1: Synthesis of 1-(4-bromo-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-phenylurea

[1733] TEA (39 mg,0 .441 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Removal of solvent followed by purification by preparative-HPLC (0.1% TFA) afforded 1-(4-bromo-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-phenylurea as a yellow solid (7.5 mg, 11.4% yield). ¹ H NMR (400 MHz, CD ₃ OD): δ 8.80 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.09 (s, 1H), 7.65 (d, J = 10.4 Hz, 1H), 7.42 (dd, J = 8.4, 1.2 Hz, 2H), 7.28 ( t, J = 8.0 Hz, 2H), 7.05–7.01 (m, 1H), 4.80–4.77 (m, 2H), 4.16 (t, J = 10.0 Hz, 2H), 3.08 (s, 3H). LCMS (M+H ⁺ ) m/z: 508.0.

Example 327:1 -(4- bromo -2- Fluoro -5-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)-3-(2-chlorophenyl)urea (compound 327) manufacturing

[1734] Step 1: Synthesis of 1-(4-bromo-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-chlorophenyl)urea

[1735] To a solution of 6-(5-amino-2-bromo-4-fluorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.129 mmol) and 1-chloro-2-isocyanatobenzene (20 mg, 0.135 mmol) in THF (20 mL) at T EA (39 mg, 0.387 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by prep-HPLC (0.1% HCl) to afford 1-(4-bromo-2-fluoro-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-chlorophenyl)urea (10.1 mg, 14.5% yield) as a yellow solid. did ¹ H NMR (400 MHz, CD ₃ OD): δ 8.83 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.12 (s, 1H), 8.08 (dd, J = 8.8, 1.6 Hz, 1H), 7.69 (d, J = 10.8 Hz, 1H), 7.43 (dd, J = 8.0, 1.6 Hz, 1H), 7.30-7.26 (m, 1H), 7.10-7.08 (m, 1H), 4.86-4.82 (m, 2H), 4.20-4.16 (m, 2H), 3.11 (s, 3H). LCMS (M+H ⁺ ) m/z: 542.1.

Example 328:1 -(4- bromo -2- Fluoro -5-(2-( oxetane -3- ylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)-3-phenylurea (Compound 328)

[1736] Step 1: Synthesis of 1-(4-bromo-2-fluoro-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-phenylurea

[1737] To a mixture of 6-(5-amino-2-bromo-4-fluorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.12 mmol, 1 eq) in THF (10 mL) TEA (5 drops, 0.6 mmol, 5 eq) and Isocyanatobenzene (1.5 drops, 0.24 mmol, 2 eq) was added. The mixture was stirred at room temperature under N2 for 2 hours. The obtained mixture was purified by preparative-HPLC (0.1% NH3.H2O) to obtain 1-(4-bromo-2-fluoro-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-phenylurea (6.4 mg, 9.7% yield) ) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.12 (s, 1H), 8.71 (s, 1H), 8.28-8.20 (m, 3H), 7.65 (d, J = 10.8 Hz, 1H), 7.43 (d, J = 7.6 Hz, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.17 (s, 1H), 6.99 (t, J = 7.6 Hz, 1H), 4.96-4.92 (m, 1H), 4.76 (t, J = 6.4 Hz, 2H), 4.54 (t, J = 6.4 Hz, 2H), 4.03-3.88 (m, 4H). LCMS (M+H ⁺ ) m/z: 550.0.

Example 329:1 -(4- bromo -2- Fluoro -5-(2-( oxetane -3- ylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)-3-(2-chlorophenyl)urea (compound 329) manufacturing

[1738] Step 1; Synthesis of 1-(4-bromo-2-fluoro-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-chlorophenyl)urea

[1739] To a solution of 6-(5-amino-2-bromo-4-fluorophenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.116 mmol) and isocyanatobenzene (19 mg, 0.122 mmol) in THF (20 mL) TEA (35 mg, 0.348 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed and purified by preparative-HPLC (0.1% NH ₃ H ₂ O) to obtain 1-(4-bromo-2-fluoro-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-chlorophenyl)urea (19.9 mg, 29.4 % yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.50 (s, 1H), 8.84 (s, 1H), 8.29-8.22 (m, 3H), 8.08 (dd, J = 8.4, 1.6 Hz, 1H), 7.69 (d, J = 10.8 Hz, 1H), 7.46 (dd, J = 8.0, 1.2 Hz, 1H), 7.31-7.26 (m, 1H), 7.18-7.15 (m, 1H), 7.05 (td, J = 8.0, 1.6 Hz, 1H), 4.97-4.94 (m, 1H), 4.79-4.76 (m, 2H), 4.56-4.53 (m, 2H), 4.04-3.97 (m, 2H), 3.93-3.88 (m, 2H). LCMS (M+H ⁺ ) m/z: 584.0.

Example 330: 1- (2-fluoro-4-methyl-5- (2- (methylamino) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-6-yl) phenyl) -3- (3- (trifluoromethyl) phenyl) urea (compound 330) manufacturing

[1740] Step 1: Synthesis of 1-(5-bromo-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea

[1741] To a solution of 5-bromo-2-fluoro-4-methylaniline (100 mg, 0.49 mmol) in DCM (9 mL) was added 1-isocyanato-3-(trifluoromethyl)benzene (100 mg, 0.539 mmol) and TEA (123 mg, 1.225 mmol) at 0°C. The mixture was stirred at 0 °C for 2 hours. Water was added. The organic layer was separated and concentrated, and the residue was purified by flash chromatography on silica gel to give 1-(5-bromo-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea (140 mg, 66% yield). LCMS (M+H ⁺ ) m/z: 391.0

[1742] Step 2: Synthesis of 1-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

[1743] 1-(5-bromo-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea (147 mg, 0.5 mmol, 1.0 equiv), Pin ₂ B ₂ (190 mg, 0.75 mmol, 1.5 equiv), KOAc (150 mg, 1.5 mmol, 3.0 equiv) in 1,4-dioxane (4 mL) v), and PdCl ₂ (dppf) (73 mg, 0.1 mmol, 20 mol %) were refluxed under N2 for 16 h. Crude 1-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 439.0

[1744] Step 4: Synthesis of 1-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

[1745] 1, 4-디옥산 (4.0 mL) 및 H ₂ O (1.0 mL) 중 1-(2-플루오로-4-메틸-5-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-3-(3-(트리플루오로메틸)페닐)우레아 (44 mg, 0.1 mmol, 1 equiv), 6-브로모-N-메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (56 mg, 0.2 mmol, 1.0 equiv), K ₂ CO ₃ (69 mg, 0.5 mmol, 3.0 equiv), 및 PdCl ₂ (dppf) (29 mg, 0.04 mmol, 40 mol %)를 60℃에서 5 시간 동안 N2 하에 교반하였다. The reaction mixture was concentrated and purified by prep-HPLC to afford 1-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (6.3 mg, 6% yield) as a solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.37 (s, 1H), 8.60 (s, 1H), 8.25 (br, 1H), 8.04 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.53-7.47 (m, 3H), 7.32 (d, J = 7.2 Hz, 1H), 7.16–7.13 (m, 2H), 4.08–3.88 (m, 4H), 2.84 (s, 3H), 2.16 (s, 3H). LCMS (M+H ⁺ ) m/z: 512.0.

Example 331:1 -(2- chlorophenyl )-3-(2- Fluoro -4- methyl -5-(2-( methylamino Preparation of )-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (Compound 331)

[1746] Step 1: Synthesis of 1-(5-bromo-2-fluoro-4-methylphenyl)-3-(2-chlorophenyl)urea

[1747] To a solution of 5-bromo-2-fluoro-4-methylaniline (150 mg, 0.735 mmol) in DCM (3 mL) was added 1-chloro-2-isocyanatobenzene (168 mg, 1.102 mmol) and TEA (185 mg, 1.837 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hours. Water was added. The organic layer was separated and concentrated and the residue was purified by flash chromatography on silica gel to give 1-(5-bromo-2-fluoro-4-methylphenyl)-3-(2-chlorophenyl)urea (130 mg, 50% yield). LCMS (M+H ⁺ ) m/z: 357.0

[1748] Step 2: Synthesis of 1-(2-chlorophenyl)-3-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

[1749] To a mixture of 1-(5-bromo-2-fluoro-4-methylphenyl)-3-(2-chlorophenyl)urea (70 mg, 0.197 mmol) in dioxane (3 mL) was added Pin2B2 (75 mg, 0.295 mmol), Pd(dppf)Cl2 (21 mg, 0.0295 mmol) and KOAc (58 mg, 0.591 mmol) It was stirred at 85°C for 4 hours. The crude 1-(2-chlorophenyl)-3-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea was used in the next step without further purification.

[1750] Step 3: Synthesis of 1-(2-chlorophenyl)-3-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea

[1751] 6-Bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine- in dioxane (3 mL) Crude 1-(2-chlorophenyl)-3-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)urea (346 mg, 0.856 mmol), Pd(dppf)Cl ₂ (78 mg, 0.106 mmol) and K ₂ CO ₃ (295 mg, 2.139 mmol) ) was added. The mixture was stirred at 85° C. for 4 hours. The mixture was concentrated to give the crude product which was purified by prep-HPLC to give 1-(2-chlorophenyl)-3-(2-fluoro-4-methyl-5-(2-(methylamino)-8 ,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea was obtained (11.1 mg, yield 3%). ^1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H), 8.75 (s, 1H), 8.25 (br, 1H), 8.11 (dd, J = 8.4, 1.6 Hz, 1H), 7.98 ( d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.0, 1.2 Hz, 2H), 7.28–7.26 (m, 1H), 7.15 (d, J = 12.0 Hz, 2H), 7.03–7.02 (m , 1H), 4.10–3.90 (m, 4H), 2.84 (s, 3H) and 2.16 (s, 3H). LCMS (M+H ⁺ ) m/z: 478.0.

Example 332:1 -(2- chlorophenyl )-3-(5-(2-( ethylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea (Compound 332)

[1752] Step 1: Synthesis of 6-bromo-N-ethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1753] To a solution of 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (420 mg, 1.41 mmol) in DCM (10 mL) was added m-CPBA (1039 mg, 4.23 mmol). The solution was stirred at room temperature under N2 for 1 hour. Ethanamine (634 mg, 8.46 mmol, 60% in water) was then added. The solution was stirred at room temperature under N2 for 1 hour. The solution was diluted with saturated NaHCO3 (30 mL) and extracted with DCM/MeOH = 10/1 (30 mL x 3). The combined organic phases were concentrated and purified by flash chromatography (DCM/MeOH = 10/1) to give 6-bromo-N-ethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (320 mg, 77% yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 296.0.

[1754] Step 2: Synthesis of 6-(5-amino-4-fluoro-2-methylphenyl)-N-ethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1755] 6-Bromo-N-ethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (150 mg, 0.51 mmol) in dioxane (6 mL) and water (1.5 mL), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- A mixture of 2-yl)aniline (128 mg, 0.51 mmol), Cs2CO3 (497 mg, 1.53 mmol) and Pd(dppf)Cl2 (75 mg, 0.102 mmol) was stirred at 100° C. under N2 for 6 h. The reaction mixture was cooled to room temperature and purified by flash chromatography (0.1%/FA/CHCN/H2O) to give 6-(5-amino-4-fluoro-2-methylphenyl)-N-ethyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (153 mg, 89% yield) as a yellow solid. LCMS (M+H+) m/z: 339.3.

[1756] Step 3: Synthesis of 1-(2-chlorophenyl)-3-(5-(2-(ethylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea hydrochloride

[1757] 1-chloro-2-isocyanatobenzene (37 mg, 0.24 mmol) was added. The reaction mixture was stirred at room temperature under N2 for 3 hours. The mixture was stirred at room temperature under N2 for 3 hours. The mixture was filtered and the filter cake was purified by preparative-HPLC (0.1%/HCl/CH3CN/H2O) to obtain 1-(2-chlorophenyl)-3-(5-(2-(ethylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea hydrochloride (19.8 mg, 15 .8% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.68 (s, 1H), 9.55 (s, 1H), 8.94-8.87 (m, 2H), 8.59-7.90 (m, 1H), 8.13-8.07 (m, 3H), 7.46 (d, J = 7.2 Hz, 1H), 7.34-7.26 (m, 2H), 7.04 (t, J = 7.2 Hz, 1H), 4.64-4.59 (m, 2H), 4.01 (t, J = 9.6 Hz, 2H), 3.48-3.42 (m, 2H), 2.16 (s, 3H), 1.23-1.15 (m, 3H). LCMS (M+H ⁺ ) m/z: 492.0.

Example 333: 1- (2-fluoro-4-methyl-5- (2- (methylamino) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-6-yl) phenyl) -3- (2-fluoro-5- (trifluoromethyl) phenyl) urea (compound 333) manufacturing

[1758] Step 1: Synthesis of 1-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

[1759] 1-fluoro-2-isocyanato-4-( Trifluoromethyl)benzene (25 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature under N2 for 1 hour. The mixture was concentrated and purified by prep-HPLC (0.1%/HCl/CH3CN/H2O) to give 1-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea (13 mg, 18% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.71 (s, 1H), 9.62 (s, 1H), 9.51 (s, 1H), 8.87 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.59-8.51 (m, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 7.53-7.48 (m, 1H), 7.40-7.38 (m, 1H), 7.34 (d, J = 12.0 Hz, 1H), 4.66-4.54 (m, 2H), 4.02 (t, J = 9.6 Hz, 2H), 2.96 (d, J = 4.4 Hz, 3H), 2.16 (s, 3H). LCMS (M+H ⁺ ) m/z: 530.3.

Example 334:1 -(2- Chloro -4- methyl -5-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)-3-(2-fluorophenyl)urea (compound 334) manufacturing

[1760] Step 1: Synthesis of 4-bromo-5-methyl-2-nitroaniline

[1761] To a solution of 5-methyl-2-nitroaniline (2.5 g, 16.4 mmol) in CHCOOH (40 mL) was added NBS (2.9 g, 16.1 mmol) dropwise at 20°C. The reaction mixture was stirred at 120 °C for 2 hours. H2O (100 mL) was added and filtered, and the solid was dried in vacuo to give 4-bromo-5-methyl-2-nitroaniline (3.3 g, 87% yield) as a yellow solid.

[1762] Step 2: Synthesis of 1-bromo-4-chloro-2-methyl-5-nitrobenzene

[1763] To a solution of 4-bromo-5-methyl-2-nitroaniline (1 g, 4.4 mmol) in CH ₃ COOH (10 mL) was added slowly a solution of NaNO ₂ in H ₂ SO ₄ (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, CuCl (1 g, 10 mmol) in HCl (5 mL) was added to the reaction solution and then the reaction mixture was stirred at 60 °C for 2 h. LCMS results indicated that the reaction performed well. H ₂ O (50 mL) was added and the reaction mixture was extracted with EA. The combined extracts were washed with brine (20 mL) and concentrated to give the crude product 1-bromo-4-chloro-2-methyl-5-nitrobenzene (0.9 g, 85% yield) as a yellow solid.

[1764] Step 3: Synthesis of 5-bromo-2-chloro-4-methylaniline

[1765] A mixture of 1-bromo-4-chloro-2-methyl-5-nitrobenzene (0.9 g, 3.6 mmol) and Fe (203 mg, 3.6 mmol), NHCl (187 mg, 3.6 mmol) in EtOH/HO (10 mL/10 mL) was stirred at 90° C. for 2 hours. Concentration in vacuo and purification on silica gel column (PE/EA 5:1) gave 5-bromo-2-chloro-4-methylaniline (800 mg, 87% yield) as a brown solid.

[1766] Step 4: Synthesis of 2-chloro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[1767] To a solution of 5-bromo-2-chloro-4-methylaniline (300 mg, 1.4 mmol), bis(pinacolato)diboron (500 mg, 2.1 mmol) and CH ₃ COOK (400 mg, 3 mmol) in dry dioxane (20 mL) was added Pd(dppf)Cl ₂ (55 mg, 0.07 mmol). The mixture was stirred at 100° C. under N ₂ for 16 hours. Concentration in vacuo gave a residue which was purified by silica gel column (PE:EA 10:1 to 1:1) to give 2-chloro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (230 mg, 60% yield) as a white solid.

[1768] Step 5: Synthesis of 6-(5-amino-4-chloro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1769] 2-chloro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (100 mg, 0.37 mmol) and 6-bromo-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyridoxyl in dioxane/H0 (10 mL/1 mL) To a mixture of midin-2-amine (103 mg, 0.37 mmol) was added Cs2CO3 (361 mg, 1.1 mmol) and Pd(dppf)Cl2 (15 mg, 0.02 mmol). The mixture was stirred overnight at 100 °C. Concentration in vacuo and purification on silica gel column (MeOH: DCM 50:1 to 10:1) gave 6-(5-amino-4-chloro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (100 mg, 53% yield) as a black solid.

[1770] Step 6: Synthesis of 1-(2-chloro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-fluorophenyl)urea

[1771] TEA (0 .2 mL) was added. The mixture was stirred overnight at 0 °C under N2. The resulting mixture was concentrated and purified by prep-HPLC (0.1% HCl) to afford 1-(2-chloro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-fluorophenyl)urea (23.6 mg, 45% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.86 (s, 1H), 8.07-8.03 (m, 3H), 7.49 (s, 1H), 7.16-7.01 (m, 3H), 4.83-4.69 (m, 2H), 4.14 (t, J = 10.0 Hz, 2H) , 3.06 (s, 3H), 2.23 (s, 3H). LCMS (M+H ⁺ ) m/z: 478.1.

Example 335: 1- (2-chloro-5- (trifluoromethyl) phenyl) -3- (2-fluoro-4-methyl-5- (2- (methylamino) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-6-yl) phenyl) urea (compound 335) manufacturing

[1772] Step 1: Synthesis of 1-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea

[1773] To a mixture of 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (40 mg, 0.12 mmol) and TEA (48 mg, 0.48 mmol) in THF (5 mL) was added 1-chloro-2-isocyanato-4-(tri Fluoromethyl)benzene (27 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature under N2 for 3 hours. The mixture was concentrated and purified by prep-HPLC (0.1%/HCl/CH3CN/H2O) to give 1-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (13 mg, 18 % yield,) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.75 (d, J = 6.4 Hz, 1H), 9.67 (s, 1H), 9.19 (s, 1H), 8.86 (s, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.53-8.37 (m, 1H), 8 .15 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.39-7.33 (m, 2H), 4.65-4.59 (m, 2H), 3.99-3.95 (m, 2H), 2.96 (d, J = 4.8 Hz, 3H), 2.16 (s, 3H). LCMS (M+H ⁺ ) m/z: 546.3.

Example 336:1 -(2- chlorophenyl )-3-(2- Fluoro -4- methyl -3-(2-( methylamino Preparation of )-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (Compound 336)

[1774] Step 1: Synthesis of 1-(2-chlorophenyl)-3-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea

[1775] 1-Chloro-2-isocyanatoben in a mixture of 6-(3-amino-2-fluoro-6-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (30 mg, 0.092 mmol) and TEA (37 mg, 0.368 mmol) in THF (4 mL) Zen (14 mg, 0.092 mmol) was added. The reaction mixture was stirred at room temperature under N2 for 16 hours. The mixture was concentrated and purified by preparative-HPLC (0.1%/HCl/CHCN/H2O) to afford 1-(2-chlorophenyl)-3-(2-fluoro-4-methyl-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (7 mg, 15% yield) as a yellow solid. did ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.94 (s, 1H), 9.42 (s, 1H), 8.88 (s, 2H), 8.61-8.58 (m, 1H), 8.24 (s, 1H), 8.19-8.12 (m, 2H), 7.48 (dd, J = 8.0, 1.2 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H),7.09-7.05 (m, 1H), 4.73-4.55 (m, 2H), 4.07-4.01 (m, 2H), 2.98 (d, J = 4.8 Hz, 3H), 2.17 (s, 3H). LCMS (M+H ⁺ ) m/z: 478.1.

Example 337: 1- (4-chloro-2-fluorophenyl) -3- (2-fluoro-4-methyl-5- (2- (methylamino) -8,9-dihydroimidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidin-6-yl) phenyl) urea (compound 337) manufacturing

[1776] Step 1: Synthesis of 1-(4-chloro-2-fluorophenyl)-3-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea

[1777] To a mixture of 4-chloro-2-fluoroaniline (23 mg, 0.16 mmol) in dry THF (20 mL) was added triphosgene (18 mg, 0.06 mmol) and TEA (0.1 mL). The reaction mixture was stirred at 0 °C for 1 hour then 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. LCMS results indicated that the reaction performed well. The mixture was concentrated in vacuo. The residue is purified by the resistance-HPLC (0.1% HCL) and purified by 1- (4-chloro-2-fluoropenyl) -3- (2-fluoro-4-methyl-5- (2- (methylamino) -8,9-dihydro Dazo [1 ', 2': 1,6] Flute? MG, 32% yield) was obtained as a yellow solid. ^1H NMR (400 MHz, CD ₃ OD): δ 8.87 (s, 1H), 8.11-8.05 (m, 3H), 7.26-7.21 (m, 2H), 7.15-7.12 (m, 1H), 4.79-4.73 (m, 2H), 4.16 (t, J = 10.0 Hz , 2H), 3.10 (s, 3H), 2.24 (s, 3H). LCMS (M+H ⁺ ) m/z: 496.1.

Example 338:1 -(2- Fluoro -4- methyl -5-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido [2,3-d]pyrimidin-6-yl)phenyl)-3-(2-fluorophenyl)urea (compound 338) manufacturing

[1778] Step 1: Synthesis of 1-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-fluorophenyl)urea

[1779] TEA (0.5 mL) and 1-fluoro-2-isocyanatobenzene (41 mg, 0. 3 mmol) was added. The solvent was removed and the residue was purified by prep-HPLC (0.1% HCl) to afford 1-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-fluorophenyl)urea (30 mg, 43% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.76 (s, 1H), 9.42 (s, 1H), 9.33 (s, 1H), 8.88 (s, 1H), 8.53-8.51 (m, 1H), 8.12-8.06 (m, 3H), 7.31 (d, J = 12.0 Hz, 1H), 7.23 (t, J = 9.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.03-7.00 (m, 1H), 4.63-4.55 (m, 2H), 4.04-4.00 (m, 2H), 2.96 (s, 3H), 2.16 (s, 3H). LCMS (M+H ⁺ ) m/z: 462.4.

Example 339:1 -(2- Fluoro -4- methyl -5-(2-( methylamino )-8,9- Dihydroimidazo[1',2':1,6]pyrido Preparation of [2,3-d]pyrimidin-6-yl)phenyl)-3-(pyridin-2-yl)urea (Compound 339)

[1780] Step 1: Synthesis of 1-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(pyridin-2-yl) urea

[1781] To a mixture of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (130 mg, 0.52 mmol) in THF (20 mL) was added triphosgene (62 mg, 0.21 mmol) slowly at 0 °C. The mixture was stirred at 0° C. to room temperature for 0.5 h under N2. Pyridin-2-amine (49 mg, 0.52 mmol) and TEA (157 mg, 1.56 mmol) were then added. The mixture was stirred at room temperature for 0.5 h under N2. LCMS results indicated that the reaction performed well. Concentration in vacuo and purification on silica gel column (PE/EA = 2:1) gave 1-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(pyridin-2-yl)urea (40 mg, 21.1% yield) as a yellow solid.

[1782] Step 2: Synthesis of 1-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(pyridin-2-yl)urea

[1783] 1-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(pyridin-2-yl)urea (40 mg, 0.11 mmol) and 6-bromo-N-methyl-8,9-dihydroimidazo[1',2' in dioxane/HO (5mL/1mL) To a mixture of :1,6]pyrido[2,3-d]pyrimidin-2-amine (30 mg, 0.11 mmol) was added Cs2CO3 (105 mg, 0.33 mmol) and Pd(dppf)Cl2 (19 mg, 0.022 mmol) and the mixture was stirred at 100° C. under N2 overnight. The mixture was concentrated in vacuo and purified by prep-HPLC (0.1% NH4CO3) to afford 1-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(pyridin-2-yl)urea (13.8 mg, 28.3% yield) as a yellow solid. obtained. ^1H NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 9.79 (s, 1H), 8.27-8.23 (m, 2H), 8.04 (d, J = 8.0 Hz, 1H), 7.78-7.74 (m, 1H), 7.48-7.35 (m, 2H) , 7.17 (d, J = 12.0 Hz, 2H), 7.04–7.01 (m, 1H), 4.11–3.89 (m, 4H), 2.84 (s, 3H), 2.17 (s, 3H). LCMS (M+H+) m/z: 445.0.

Example 340: N-(3-fluoro-4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (compound 340) manufacturing

[1784]

[1785] Step 1: Synthesis of N-(4-bromo-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide

[1786] A mixture of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (223 mg, 1.0 mmol) in SOCl ₂ (3 mL) was stirred at 70° C. for 2 h. The reaction mixture was concentrated and a solution of 4-bromo-3-fluoroaniline (200 mg, 1.1 mmol) and TEA (500 mg 5.0 mmol) in DCM (3 mL) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 3 hours. Concentration and flash purification (PE: EA=3:1~1:1) gave N-(4-bromo-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (180 mg) as a white solid. LCMS (M+H ⁺ ) m/z: 394.9.

[1787] Step 2: Synthesis of N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide

[1788] N-(4-bromo-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (147 mg, 0.5 mmol, 1.0 equiv), Pin ₂ B ₂ (190 mg, 0.75 mmol, 1.5 equiv), KOAc (150 mg, 1.5 mmol, 3 .0 equiv), and PdCl ₂ (dppf) (73 mg, 0.1 mmol, 20 mol %) was refluxed under Ar for 16 h. The reaction mixture was used in the next step without further purification. LCMS (M+H ⁺ ) m/z: 443.0

[1789] Step 3: Synthesis of N-(3-fluoro-4-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide

[1790] 1, 4-디옥산 (4.0 mL) 및 H ₂ O (1.0 mL) 중 N-(3-플루오로-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-N-(4-플루오로페닐)시클로프로판-1,1-디카르복스설폰아미드 (crude, 0.2 mmol, 1 equiv), 6-브로모-N-메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (56 mg, 0.2 mmol, 1.0 equiv), K ₂ CO ₃ (82 mg, 0.6 mmol, 3.0 equiv), 및 PdCl ₂ (dppf) (29 mg, 0.04 mmol, 20 mol %)의 혼합물을 85℃에서 2시간 동안 Ar 하에 교반하였다. The reaction mixture was purified by HPLC (NH ₄ HCO ₃ ) to give N-(3-fluoro-4-(2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (11.7 mg) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.31 (s, 1H), 10.00 (s, 1H), 8.26-8.20 (m, 1H), 7.69-7.61 (m, 3H), 7.55 (t, J = 8.4 Hz, 1H), 7.46-7.44 (m, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.15 (t, J = 8.8 Hz, 2H),4.04-3.92 (m, 4H), 2.83 (s, 3H), 1.46-1.44 (m, 4H). LCMS (M+H ⁺ ) m/z: 516.0.

Example 341: N-(4-fluoro-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (compound 341) manufacturing

[1791] Step 1: Synthesis of N-(3-bromo-4-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide

[1792] A solution of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (200 mg, 0.6 mmol) in SOCl ₂ (3 mL) was stirred at 60° C. for 1 hour. The reaction mixture was concentrated to give a crude solid. A solution of 3-bromo-4-fluoroaniline (171 mg, 0.9 mmol) and TEA (182 mg, 1.8 mmol) in DCM (5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. LCMS showed the reaction to be complete. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL*3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ and concentrated to give a white solid which was purified by chromatography column (PE:EA=4:1) to give N-(3-bromo-4-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (300 mg, 84% yield). LCMS (M+H ⁺ ) m/z: 394.8

[1793] Step 2: Synthesis of N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide

[1794] Pin2B2 (185 mg, 0.73 mmol), KOAc (142 mg, 1.46 mmol) and Pd(dppf)Cl ₂ (51 mg, 0.0 7 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 110 °C for 18 hours. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by chromatography column (PE:EA=2:1) to obtain N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfone The amide (170 mg, 53% yield) was obtained as a white solid. LCMS (M+H ⁺ ) m/z: 443.0

[1795] Step 3: Synthesis of N-(4-fluoro-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide

[1796] 디옥산 (4 mL) 및 H ₂ O (1 mL) 중 N-(4-플루오로-3-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)-N-(4-플루오로페닐)시클로프로판-1,1-디카르복스설폰아미드 (41 mg, 0.1 mmol)의 용액에 6-브로모-N-메틸-8,9-디히드로이미다조[1',2':1,6]피리도[2,3-d]피리미딘-2-아민 (27 mg, 0.1 mmol), K ₂ CO ₃ (28 mg, 0.2 mmol) 및 Pd(dppf)Cl ₂ (7 mg, 0.01 mmol)를 질소 분위기 하에 첨가하였다. The mixture was stirred at 90° C. for 6 hours. LCMS showed the reaction to be complete. The mixture was diluted with water (10 mL) and extracted with EA (10 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by chromatography column (PE:EA=1:2) to obtain N-(4-fluoro-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4-fluoro Obtained rophenyl)cyclopropane-1,1-dicarboxsulfonamide (4.5 mg, 8% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.44-8.41 (m, 1H), 8.17 (s, 1H), 7.84-7.81 (m, 1H), 7.68-7.65 (m, 1H), 7.58-7.55 (m, 2H), 7.31 (t, J = 9.2 Hz, 1H), 7.09 (t, J = 8.8 Hz, 2H), 4.80–4.65 (m, 2H), 4.15 (t, J = 10.0 Hz, 2H), 3.09 (s, 3H), 1.66–1.63 (m, 4H). LCMS (M+H ⁺ ) m/z: 516.0.

Example 342: N-(4-chloro-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (compound 342) manufacturing

[1797] Step 1: Synthesis of 6-(5-amino-2-chlorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine

[1798] A mixture of 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (65 mg, 0.26 mmol), CsCO ₃ (9.5 g, 97 mmol), and Pd(dppf)Cl ₂ (8 mg, 0.01 mmol) in dioxane (10 mL) and H ₂ O (1 mL) was degassed and It was charged with N ₂ three times and then stirred at 90° C. for 16 h under N ₂ . The reaction mixture was concentrated and purified by prep-HPLC (0.1% NH ₃ ^. H ₂ O) to give 6-(5-amino-2-chlorophenyl)-N-methyl-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-2-amine (50 mg, 59 % yield) as a yellow solid. LCMS (M+H ⁺ ) m/z: 327. 1.

[1799] Step 2: Synthesis of N-(4-chloro-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide

[1800] 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (45 mg, 0.20 mmol), 6-(5-amino-2-chlorophenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.18 mmol) in DMF (5 mL), and To a solution of HATU (105 mg, 0.28 mmol) was added DIEA (70 mg, 0.55 mmol). The resulting mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was added slowly to water (40 mL), stirred at room temperature for 30 minutes and then filtered. The collected cake was purified by preparative-HPLC (0.1% NH ₃ ^.H ₂ O) to obtain N-(4-chloro-3-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (5.5 mg, 5.6 % yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.17 (s, 1H), 9.99 (s, 1H), 8.24-8.22 (m, 1H), 7.70-7.68 (m, 1H), 7.66-7.61 (m, 3H), 7.46-7.40 (m, 2H), 7.19–7.11 (m, 3H), 4.07–3.85 (m, 4H), 2.84 (s, 3H), 1.48–1.42 (m, 4H). LCMS (M+H ⁺ ) m/z: 532.2.

Example 343: N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (compound 343) manufacturing

[1801] The preparation of 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 139.

[1802] Step 1: Synthesis of N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide

[1803] 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (55 mg, 0.25 mmol), 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (80 mg, 0 .25 mmol), and HATU (190 mg, 0.50 mmol) was added DIEA (65 mg, 0.50 mmol). The resulting mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was quenched with water (20 mL) and extracted with DCM (20 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product which was purified by Pre-HPLC (0.1% NH ₃ .H ₂ O) to obtain N-(2-fluoro-4-methyl-5-(2-(methylamino)-8,9-dihydroimidazo[1’,2’:1,6]pyrido[2,3-d]pyrimidin-6-yl) Phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (21.7 mg, 16.5% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.51 (s, 1H), 9.93 (s, 1H), 8.21-8.17 (m, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.61-7.57 (m, 2H), 7.40-7.39 (m, 1H), 7.18-7.13 (m, 3H), 7.07 (s, 1H), 4.00-3.95 (m, 2H), 3.89 (t, J = 8.8 Hz, 2H), 2.83 (d, J = 4.0 Hz, 3H), 2.18 (s, 3H), 1.58-1.54 (m, 4H). LCMS (M+H ⁺ ) m/z: 530.3.

Example 344: N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (compound 344) manufacturing

[1804]

[1805] The preparation of 6-(5-amino-4-fluoro-2-methylphenyl)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine is described in Example 178.

[1806] Step 1: Synthesis of N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide

[1807] 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (36.6 mg, 0.164 mmol), 6-(5-amino-4-fluoro-2-methylphenyl)-N-(oxetan-3-yl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine in DMF (4.0 mL) To a solution of -2-amine (60 mg, 0.164 mmol) and HATU (125 mg, 0.328 mmol) was added DIEA (42 mg, 0.328 mmol). The resulting mixture was stirred at room temperature for 3 hours under N ₂ . The reaction mixture was added to water (40 mL) and extracted with DCM (30 mL x3). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (DCM:MeOH=12:1, +0.1% NH ₃ -MeOH), then triturated with CH3CN (5.0 mL) to N-(2-fluoro-4-methyl-5-(2-(oxetan-3-ylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenyl)-N-(4 -Fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (32.6 mg, 34.7% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.53 (s, 1H), 9.92 (s, 1H), 8.21 (s, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.60-7.57 (m, 2H), 7.18-7.09 (m, 4H), 4.94-4.91 (m, 1H), 4.75 (t, J = 6.0 Hz, 2H), 4.53 (t, J = 6.0 Hz, 2H), 4.02-3.98 (m, 2H), 3.92-3.87 (m, 2H), 2.17 (s, 3H), 1.61-1.51 (m, 4H). LCMS (M+H ⁺ ) m/z: 572.3.

Example 345: N-(4-fluorophenyl)-N-(4-((2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)cyclopropane-1,1-dicarboxsulfonamide (compound 345) manufacturing

[1808] Step 1: Synthesis of N-(4-fluorophenyl)-N-(4-((2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)cyclopropane-1,1-dicarboxsulfonamide

[1809] To a mixture of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (223 mg, 1.0 mmol) in CHCl ₃ (1.0 mL) was added SOCl ₂ (1.0 mL) at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. The reaction was concentrated to give crude 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride. To a mixture of 6-(4-aminophenoxy)-N-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (60 mg, 0.2 mmol), DIPEA (78 mg, 0.6 mmol) in DCM (5.0 mL), crude 1-((4-fluorophenyl)carbamoyl)cyclo in DCM (1.0 mL) A solution of propane-1-carbonyl chloride (58 mg, 0.24 mmol) was added. The reaction was stirred at 25 °C for 2 hours. The reaction was concentrated and purified by HPLC (NH ₄ HCO ₃ ) to give N-(4-fluorophenyl)-N-(4-((2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)cyclopropane-1,1-dicarboxsulfonamide (47.1 mg) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.05 (d, J = 17.2 Hz, 2H), 8.14 (s, 1H), 7.65-7.58 (m, 4H), 7.31-7.29 (m, 1H), 7.17-7.12 (m, 2H), 7.04-7.0 0 (m, 2H), 6.80–6.75 (m, 1H), 4.04–3.92 (m, 4H), 2.81 (s, 3H), 1.45 (s, 4H). LCMS (M+H ⁺ ) m/z: 514.0.

Example 346: N-(3-fluoro-4-((2-(methylamino)-8,9-dihydroimidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (compound 346) manufacturing

[1810] Step 1: Synthesis of ethyl 2-(4-acetamido-2-fluorophenoxy)acetate

[1811] To a mixture of ethyl 2-(4-amino-2-fluorophenoxy)acetate (3.65 g, 17.14 mmol) and DIEA (6.63 g, 51.42 mmol) in dry DCM (40 mL) was added acetyl chloride (2.02 g, 25.71 mmol) dropwise under N ₂ at 0 °C. The resulting mixture was stirred at 0 °C for 30 min, quenched with saturated NaHCO ₃ (30 mL) and extracted with DCM (50.0 mLx2). The combined organic phases were washed with brine (50.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (PE: EA=1:1) to give ethyl 2-(4-acetamido-2-fluorophenoxy)acetate (4.0 g, 91.5% yield) as an off-white solid. LCMS (M+H ⁺ ) m/z: 256.2.

[1812] Step 2: Synthesis of N-(3-fluoro-4-((2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)acetsulfonamide

[1813] A mixture of 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (973 mg, 5.76 mmol), ethyl 2-(4-acetamido-2-fluorophenoxy)acetate (1.64 g, 6.04 mmol) and K ₂ CO ₃ (2.39 g, 17.28 mmol) in DMA (40 mL) at 120 °C. Stirred under N ₂ for 16 hours. The reaction mixture was cooled to room temperature, added to water (400 mL), and the pH was adjusted to 3.0-4.0 with hydrochloric acid (3M). The mixture was stirred at room temperature for 30 minutes and filtered. The collected cake was washed with water (100 mL) and triturated with CHCN (10 mL) to give N-(3-fluoro-4-((2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)acetsulfonamide (1.26 g, 60.8% yield) as a brown solid. LCMS (M+H+) m/z: 360.9.

[1814] Step 3: Synthesis of N-(3-fluoro-4-((7-((2-hydroxyethyl)amino)-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)acetsulfonamide

[1815] N-(3-fluoro-4-((2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)acetsulfonamide (1.35 g, 3.75 mmol), 2-aminoethane-1-ol (422 mg, 5.62 mmol) and PyBOP (2.92 g) in DMF (20 mL) , 5.62 mmol) was added DIEA (967 mg, 7.50 mmol). The resulting mixture was stirred at room temperature for 0.5 h under N ₂ . The reaction mixture was added to water (200 mL), stirred at room temperature for 30 minutes and filtered. The collected cake was washed with water (50 mL) and triturated with CHCN (15 mL) to give N-(3-fluoro-4-((7-((2-hydroxyethyl)amino)-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)acetsulfonamide (1.41 g, 93.4% yield) as a gray solid. LCMS (M+H ⁺ ) m/z: 404.1

[1816] Step 4: Synthesis of N-(3-fluoro-4-((2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)acetsulfonamide

[ ₁₈₁₇ ] To a mixture of N-(3-fluoro-4-((7-((2-hydroxyethyl)amino)-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)acetsulfonamide (1.41 g, 3.50 mmol) in CHCl 3 (35.0 mL) was added SOCl ₂ (2.08 g, 17.50 mmol). The resulting mixture was stirred at 70° C. for 16 h under N ₂ . The reaction mixture was concentrated and added to saturated NaHCO ₃ (50.0 mL), stirred at room temperature for 30 minutes, then filtered. The collected cake was washed with water (50 mL) and triturated with CHCN (30 mL) to give N-(3-fluoro-4-((2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)acetsulfonamide (1.235 g, 91.7% yield) as a gray solid. LCMS (M+H ⁺ ) m/z: 386.1

[1818] Step 5: Synthesis of 3-fluoro-4-((2-(methylthio)-8,9 dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)aniline

[1819] A mixture of N-(3-fluoro-4-((2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)acetsulfonamide (1.235 g, 3.21 mmol) in aq.HCl (3.0 M, 40.0 mL) at 80°C for 4 hours in N Stirred under ₂ . The reaction mixture was cooled to 0°C, adjusted to pH=7-8 by adding aq.NaOH (4.0 M), stirred at room temperature for 30 minutes, and filtered. The collected cake was washed with water (50 mL) and triturated with CHCN (15 mL) to give 3-fluoro-4-((2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)aniline (700 mg, 63.6% yield) as a gray solid. LCMS (M+H ⁺ ) m/z: 344.1.

[1820] Step 6: Synthesis of N-(3-fluoro-4-((2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide

[1821] 3-Fluoro-4-((2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)aniline (80 mg, 0.233 mmol), 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (52 mg) in DMF (4.0 mL) , 0.233 mmol) and HATU (133 mg, 0.350 mmol) was added DIEA (60 mg, 0.466 mmol). The resulting mixture was stirred at room temperature for 16 hours under N ₂ . The reaction mixture was added to water (40 mL), stirred at room temperature for 30 minutes, and filtered. The collected cake was purified by column chromatography (DCM/MeOH=20/1) to obtain N-(3-fluoro-4-((2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (80 mg, 62.5% aqueous rate) was obtained as a brown solid. LCMS (M+H ⁺ ) m/z: 549.1.

[1822] Step 7: Synthesis of N-(3-fluoro-4-((2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide

[1823] m-CP to a mixture of N-(3-fluoro-4-((2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (80 mg, 0.146 mmol) in DCM (5.0 mL) BA (64 mg, 0.438 mmol) was added at 0 °C. The resulting mixture was stirred at 0°C for 0.5 hour. The reaction mixture was concentrated to give crude N-(3-fluoro-4-((2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (144 mg) as a yellow solid. LCMS (M+H ⁺ ) m/z: 565.1

[1824] Step 8: Synthesis of N-(3-fluoro-4-((2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide

[1825] Crude N-(3-fluoro-4-((2-(methylsulfinyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxsulfonamide (144 mg, 0.146 mmol) in THF (2.5 mL) To the mixture was added Me-NH ₂ (2.0 M, 0.37 mL, 0.73 mmol). The resulting mixture was stirred at room temperature for 4.0 hours. The reaction mixture was poured into water (30 mL) and extracted with DCM (50 mLx3). The combined organic phases were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH=10:1) then triturated with EA (5.0 mL) to give N-(3-fluoro-4-((2-(methylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarbox The sulfonamide (31.3 mg, 23.1% yield over 2 steps) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.23 (s, 1H), 10.00 (s, 1H), 8.11 (s, 1H), 7.77 (dd, J = 13.6, 2.4 Hz, 1H), 7.64-7.61 (m, 2H), 7.35 (d, J = 9.2 Hz, 1H), 7.24-7.23 (m, 1H), 7.19-7.12 (m, 3H), 6.65 (s, 1H), 4.36-4.33 (m, 4H), 2.79 (d, J = 4.0 Hz, 3H), 1.45-1.44 (m, 4H). LCMS (M+H ⁺ ) m/z: 532.3.

[1826] The foregoing description of the compounds, uses and methods described herein will enable those skilled in the art to make and use the compounds, uses and methods described herein, but those skilled in the art will understand and appreciate that many variations, combinations and equivalents of the specific examples, methods and examples described herein exist. Thus, the compounds, uses and methods provided herein are not limited to the foregoing embodiments, methods or examples, but rather include all embodiments and methods within the scope and spirit of the compounds, uses and methods provided herein.

[1827] All references disclosed herein are incorporated by reference in their entirety.

[1828] The in vitro and in vivo activities of the compounds of formula (I) were determined using the following procedure.

biological Example B1

[1829] In vitro kinase assay

[1830] The effects of the compounds on the activities of SRC and PAK1 kinase were evaluated. SRC and PAK1 kinase enzymes were purchased from Carna Biosciences.

[1831] A 20 mM stock was prepared by dissolving the test compound in 100% DMSO. Compounds were stored at -20 °C and protected from light. 100x solutions of compounds were prepared, in which 4-fold serial dilutions were performed to achieve a total of 6 concentrations. Saracatinib was used as a positive control for the SRC assay and FRAX597 was used as a positive control for the PAK1 assay. For positive controls, 3-fold serial dilutions were made to achieve a total of 10 concentrations. 10 μL 1x Kinase buffer was used as a negative control.

[1832] First, 250 nL of compound from each dilution was transferred to the wells of a 384-well plate. PAK1 and SRC kinase were diluted to 2.5x final concentration in 1x kinase buffer. Then, 10 μL of the enzyme mixture was added to the 384-well plate and the enzyme and compound were pre-incubated for 10 minutes at room temperature. A substrate mixture containing ATP and kinase substrate at a final concentration of 1.67x was prepared in 1x kinase buffer. Then, 15 μL of the substrate mixture was added to the 384-well plate and reacted at room temperature for 30 and 60 minutes. The reaction was stopped by adding 30 μL of stop buffer and the conversion was read using a Caliper EZ Reader.

[1833] Percent inhibition is determined according to the equation:

In the formula, "sample conversion %" is the conversion percentage value of the sample;

"Minimum conversion %" is the average conversion value of the negative control. "Max Conversion %" is the average conversion percentage value of the positive control.

[1834] GraphPad Prism software (version 5, Informer Technologies, Inc., Los Angeles, CA, USA) was used to fit dose-response curves, and the IC50 values for each compound were log (inhibitor) vs. Calculated by reaction.

Y=bottom + (top-bottom)/(1+10^((LogIC50-X)*hillslope))

[1835] Table A1 shows the IC50 values of each test compound for SRC and PAK1.

[1836] The effect of compounds on the activity of HPK1 (MAP4K1) kinase was evaluated by Lantha screen assay.

[1837] 1. Prepared 1x Kinase Buffer (50 mM HEPES, pH 7.5, 10 mM MgCl2, 4 mM DTT, 0.01% Tween-20, and 0.01% BSA);

[1838] 2. Preparation of compounds and assay plates:

[1839] 2-1) The compound was diluted to 100X of the desired final highest inhibitor concentration in a 100% DMSO reaction. For example, if a compound was tested at 5 μM, a 500 μM solution of DMSO was prepared at this step.

[1840] 2-2) For each test compound, the compound was transferred from the test tube to one well on a 96-well storage plate, and 10 μl was transferred to 70 μl of 100% DMSO in the next well, so that a total of 6 concentrations were serially diluted.

[1841] 2-3) 100 μl of 100% DMSO was added to two empty wells and used as no-compound control and null enzyme control in the same 96-well plate. The resulting plate was designated as the source plate.

[1842] 2-4) 40 μl of the compound from the source plate was transferred to a new 384-well echo plate as an intermediate plate. 100nl of each well of the 384-well Echo plate was transferred to the 384-well assay plate in duplicate. For example, A1 of the 384-well echo plate was transferred to A1 and A2 of the 384-well plate. Transfer A2 of the 384-well Echo plate to A3 and A4 of the 384-well plate, and so on;

[1843] 3. Kinase reaction: A MAP4K1 solution was prepared in 1x kinase buffer at twice the final concentration of each reagent in the assay. Except for the control wells without enzyme (5 μl of 1x kinase buffer was added instead), 5 μl of kinase solution was added to each well of the assay plate. The plate was then shaken and incubated for 10 minutes at room temperature. A substrate solution of Fluorescein-PKC and ATP contained in 1x kinase reaction buffer was prepared at twice the final concentration of each reagent desired in the assay. The reaction was started by adding 5 μl of substrate solution to each well of the assay plate. The plate was shaken, covered and incubated for 90 minutes at room temperature.

[1844] Kinase detection: A detection solution at twice the final concentration was prepared in antibody dilution buffer. The reaction was stopped by adding 10 μl of detection solution to each well of the assay plate. The mixture was briefly mixed by centrifugation and incubated at room temperature for 60 minutes before reading fluorescence in a plate reader. Data were collected on an Envision with excitation at 340 nm and emission at 520 nm and 495 nm.

[1845] Table A2 shows the IC50 values of each test compound against HPK1.

Table 2

[1846] The effect of compounds on the activities of cKit, RET and AXL kinases was evaluated by mobility shift assay.

[1847] 1. 1x kinase base buffer and stop buffer were prepared for the kinase test.

[1848] 1-1) 1x kinase base buffer (50 mM HEPES, pH 7.5, 0.01% Triton X-100)

[1849] 1-2) Stop buffer (100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, 50 mM EDTA)

[1850] 2. Preparation of compounds and assay plates: Compounds were reacted with 100% DMSO and diluted to 50X the desired final highest inhibitor concentration. 100 μl of this compound dilution was transferred to the wells of a 96-well plate. For example, if the highest desired concentration is 5 μM, a 250 μM complex DMSO solution was prepared at this step. For all compounds, the compounds were serially diluted to a total of 5 concentrations by transferring 10 μl to 70 μl of 100 DMSO in the next well or the like. 100 μl of 100% DMSO was added to two empty wells of the same 96-well plate to serve as compound control and enzyme control. This plate was designated as the source plate. The middle plate was prepared by transferring 10 μl of compounds from the source plate to a new 96-well plate as a middle plate, adding 90 μl of 1x kinase buffer to each well of the middle plate, then mixing the compounds in the middle plate on a shaker for 10 minutes. 5 μl of each well from the 96-well middle plate was transferred to a 384-well plate in duplicate. For example, A1 of a 96-well plate was transferred to A1 and A2 of a 384-well plate. A2 of the 96-well plate was transferred to A3 and A4 of the 384-well plate, and so on.

[1851] 4. Kinase reaction: The assay plate already contains 5 μl of compound in 10% DMSO. A 2.5x enzyme solution was prepared by adding kinase (cKit, RET or AXL) and DTT to 1x kinase base buffer. The 2.5x enzyme solution was transferred to the assay plate (by adding 10 μl of 2.5x enzyme solution to each well of a 384-well assay plate). Plates were incubated for 10 minutes at room temperature. A 2.5x peptide solution was prepared by adding FAM-labeled peptide, ATP, and MgCl2 to 1x kinase base buffer. The 2.5x peptide solution was added to the assay plate by adding 10 μl of the 2.5x peptide solution to each well of the 384-well assay plate. Plates were incubated at 28° C. for the indicated times. The reaction was stopped by adding 25 μl of stop buffer. Data was collected in Caliper.

[1852] Table A3 shows the IC ₅₀ values of each test compound for c-Kit.

Table 3.

[1853] Table 4 shows the IC ₅₀ values for each compound tested for RET.

[1854] Table 5 shows the IC ₅₀ values for each compound tested against Axl.

biological Example B2

[1855] MDCK-MDR1 permeability assay

[1856] MDCK-MDR1 cells are derived from transfection of Madin Darby canine kidney (MDCK) cells with the MDR1 gene, a gene encoding the efflux protein, P-glycoprotein. This cell line is ideal for identifying substrates of P-gp with or without inhibitors. Cells are seeded into Multiscreen™ plates 4 days before the experiment to form a confluent monolayer. On day 4, test compounds (1-30 μM concentration) are added to the apical side of the membrane and the migration of the compound across the monolayer is monitored for 120 min. To study drug efflux, it is also necessary to investigate the transport of compounds from the basolateral to the apical compartment and to calculate the efflux ratio.

[1857] The coefficient of permeability (P _app ) is given by the equation:

P _app = [(dQ/dt)/C ₀ x A]

where dQ/dt is the permeation rate of the drug across the cell, C ₀ is the donor compartment concentration at time 0 and A is the area of the cell monolayer.

[1858] The outflow ratio is obtained from the average peak-to-basal (AB) P _app data and basolateral-to-apical (BA) P _app data.

Outflow Ratio = P _app (BA)/P _app (AB)

[1859] Table B summarizes the permeability of compounds in the MDCK-MDR1 assay.

biological Example B3

[1860] mouse pharmacokinetic studies

[1861] The pharmacokinetic properties of compound 1 were studied in CD-1 mice via intravenous and oral administration using standard protocols. Test articles were formulated as clear solutions or fine suspensions in 20% hydroxypropyl-beta-cyclodextrin. Table D shows the pharmacokinetic characteristics of Compound 1 by intravenous injection in mice.

[1862] Table E shows plasma exposure by oral administration of Compound 1 in mice. e.

biological Example B4

[1863] In vivo pharmacokinetic studies

[1864] The activity of a compound of formula (I) in vivo can be determined by the amount of tumor growth inhibition by a test compound relative to a control. The tumor growth inhibitory effect of various compounds is described by Corbett TH, et al., "Tumor Induction Relationships in Development of Transplantable Cancers of the Colon in Mice for Chemotherapy Assays, with a Note on Carcinogen Structure", Cancer Res., 35, 2434-2439 (1975) and Corbett TH, et al., "A Mouse Colon-tumor Model for Experimental Therapy", Cancer Chemother. Rep. (Part 2)", 5, 169-186 (1975)]에 기재된 방법을 약간 변형하여 측정한다. 0.1ml RPMI 1640 배지에 현탁시킨 100만 내지 500만 대수기 배양 종양 세포(인간 A375 흑색종 또는 HT-29 결장직장 암 세포)를를 왼쪽 옆구리에 피하 주사하여 종양을 유도한다. 종양이 만져질 수 있을 만큼 충분한 시간이 경과한 후(크기 100-150mm ³ /직경 5-6mm) 시험 동물(BALB/c 누드 암컷 마우스)에게 테스트 화합물(20% 하이드록시프로필-베타-사이클로덱스트린에 10~15mg/ml의 농도로 제형화)을 1일 1~2회 경구 투여함으로써 처리한다. 항종양 효과를 알아보기 위해, 2개의 직경에 걸쳐 버니어 캘리퍼스를 사용하여 종양을 밀리미터 단위로 측정하고, Geran, RI, et al. "Protocols for Screening Chemical Agents and Natural Products Against Animal Tumors and Other Biological Systems", Third Edition, Cancer Chemother. Rep., 3, 1-104 의 방법에 따라, 종양 크기(mm3)를 하기 식을 이용하여 계산한다: 종양 크기 (mm ³ ) = (길이 x 너비 ² )/2. 결과는 다음 공식에 따라 억제율 백분율로 표현된다: 억제(%) = (TuW _대조군 -TuW _테스트 )/TuW _대조군 x 100%. 종양 이식의 측면 부위는 다양한 화학요법제에 대해 재현 가능한 용량/반응 효과를 제공하며 측정 방법(종양 직경)은 종양 성장 속도를 평가하는 신뢰할 수 있는 방법이다.

[1865] Administration of the compounds of the present invention (hereinafter "active compound(s)") can be accomplished by any method capable of delivering the compound to the site of action. These methods include oral route, intraduodenal route, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.

[1866] A pharmaceutical composition may be used, for example, for oral administration as a tablet, capsule, pill, powder, sustained release preparation, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or as a suppository It may be in a form suitable for rectal administration. The pharmaceutical composition may be in unit dosage form suitable for single administration of precise dosages. A pharmaceutical composition will contain a compound according to the present invention as an active ingredient and a conventional pharmaceutical carrier or excipient. In addition, other medicines or drugs, carriers, adjuvants, and the like may be included.

[1867] The examples and formulations provided below further illustrate and illustrate the compounds of the present invention and methods for preparing such compounds. It should be understood that the scope of the present invention is not limited in any way by the scope of the following examples and formulations. In the following examples, molecules with a single chiral center are present as racemic mixtures unless otherwise specified. Molecules with two or more chiral centers exist as racemic mixtures of diastereomers unless otherwise specified. Single enantiomers/diastereomers can be obtained by methods known to those skilled in the art.

Claims (45)

Compounds of formula (I):

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof:
during the ceremony,
G ¹ is N or CR ^a ;
G ² is N or CR ^b ;
n is 1 or 2;
m is 0, 1, 2 or 3;
R ^a and R ^b are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted C ₁ -C ₆ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ alkylamino, and optionally substituted aryloxy;
each R ¹ is independently selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;
or two R ¹ groups together with the carbon atoms to which they are connected form a 4- to 7-membered carbocyclic or heterocyclic ring optionally substituted by one or more R ^a groups;
R ² 는 수소, 임의 치환된 C ₁ -C ₆ 알킬, 임의 치환된 C ₁ -C ₆ 알킬-O, 임의 치환된 C ₁ -C ₆ 알킬-S, 임의 치환된 C ₁ -C ₆ 알킬-SO ₂ , 임의 치환된 C ₁ -C ₆ 알킬-NR ^a , 임의 치환된 C ₂ -C ₆ 알케닐, 임의 치환된 C ₂ -C ₆ 알키닐, 임의 치환된 아릴, 임의 치환된 아릴-O, 임의 치환된 아릴-S, 임의 치환된 아릴-SO ₂ , 임의 치환된 아릴-NR ^a , 임의 치환된 헤테로아릴, 임의 치환된 헤테로아릴-O, 임의 치환된 헤테로아릴-S, 임의 치환된 헤테로아릴-SO ₂ , 임의 치환된 헤테로아릴-NR ^a , 임의 치환된 시클로알킬, 임의 치환된 시클로알킬-O, 임의 치환된 시클로알킬-S, 임의 치환된 시클로알킬-SO ₂ , 임의 치환된 시클로알킬NR ^a , 임의 치환된 헤테로시클릴, 임의 치환된 헤테로시클릴-O, 임의 치환된 헤테로시클릴-S, 임의 치환된 헤테로시클릴-SO ₂ , 및 임의 치환된 헤테로시클릴-NR ^a 로 이루어진 군으로부터 선택되며;
R ³ is selected from the group consisting of hydrogen, halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy;
R ⁴ is selected from the group consisting of:
(i) hydrogen;
(ii) C ₁ -C ₆ alkyl optionally substituted with one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, hydroxyl, heteroaryl, and optionally substituted heterocyclyl;
(iii) heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, acryloyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted C ₁ -C ₆ alkyl-NR ^a , and optionally substituted heterocyclyl;
(iv) aryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -C(O)O(C ₁ -C- ₆ alkyl), acryloylamino, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C 1 -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted C _{1 -C 6} alkyl-NR ^a , and optionally substituted heterocyclyl;
(v) heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted C ₁ -C ₆ alkyl-NR ^a , optionally substituted heteroaryl, and optionally substituted heterocyclyl;
(vi) carbonyl substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -NRa(C ₁ -C ₆ alkoxy), and optionally substituted heteroaryl; and
(vii) —SO ₂ (C ₁ -C ₆ alkyl);
R ⁵ is hydrogen, C ₁ -C ₆ alkyl, or heterocyclyl;
or R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
provided that R ² is 2,6-dichloro-3,5-dimethoxyphenyl:
R ⁴ is selected from the group consisting of:
(i) hydrogen;
(ii) C ₁ -C ₆ alkyl optionally substituted with one or more groups selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, hydroxyl, heteroaryl, and optionally substituted heterocyclyl;
(iii) heterocyclyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, acryloyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;
(iv) aryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -C(O)O(C ₁ -C- ₆ alkyl), optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl;
(v) heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
(vi) carbonyl substituted with C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, —NRa(C ₁ -C ₆ alkoxy), and optionally substituted heteroaryl; and
(vii) —SO ₂ (C ₁ -C ₆ alkyl);
R ⁵ is hydrogen, C ₁ -C ₆ alkyl, or heterocyclyl;
or R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. The compound according to claim 1, wherein G ¹ is N, or a pharmaceutically acceptable salt, solvate or isotope derivative thereof. The compound according to claim 1, wherein G ¹ is CR ^a , or a pharmaceutically acceptable salt, solvate or isotope derivative thereof. The compound according to claim 3, wherein R ^a is hydrogen, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. The compound according to any one of claims 1 to 4, wherein G ² is N, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. The compound according to any one of claims 1 to 4, wherein G ² is CR ^b , or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 7. The compound according to claim 6, wherein R ^b is hydrogen, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 2. The compound of claim 1, wherein the compound has formula (I-1a)

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof: wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, and n are as defined in Formula (I). The compound according to any one of claims 1 to 8, wherein n is 1, or a pharmaceutically acceptable salt, solvate or isotope derivative thereof. The compound according to any one of claims 1 to 8, wherein n is 2, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 2. The compound of claim 1, wherein the compound has formula (I-2a) or (I-2b)

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof: wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and m are as defined in Formula (I). The compound according to any one of claims 1 to 11, wherein m is 0, or a pharmaceutically acceptable salt, solvate or isotope derivative thereof. 12. A compound according to any one of claims 1 to 11, wherein each m is 1 and R ¹ is independently selected from the group consisting of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 12. The compound of claim 1 wherein each m is 1 and R ¹ independently consists of halogen, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy. A compound selected from the group, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. The compound of claim 1, wherein the compound has formula (I-3a) or (I-3b)

or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof: wherein R ² , R ³ , R ⁴ , and R ⁵ are as defined in formula (I). 16. The compound according to any one of claims 1 to 15, wherein R ² is hydrogen, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 16. The compound or pharmaceutically acceptable salt, solvate or isotopic derivative thereof according to any one of claims 1 to 15, wherein R ² is optionally substituted C ₁ -C ₆ alkyl, optionally substituted C _{2 -C 6} alkenyl, or optionally substituted C 2 -C ₆ alkynyl. 16. The compound according to any one of claims 1 to 15, wherein R ² is optionally substituted aryl, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. no content 16. The compound according to any one of claims 1 to 15, wherein R ² is optionally substituted heteroaryl, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 15. The compound according to any one of claims 1 to 14, wherein R ² is optionally substituted heterocyclyl, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 23. The method of claim 22, wherein R ² is H,






A compound selected from the group consisting of, or a pharmaceutically acceptable salt, solvate or isotope derivative thereof. 23. The compound according to any one of claims 1 to 22, wherein R ³ is hydrogen, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 23. The compound according to any one of claims 1 to 22, wherein R ⁴ is C ₁ -C ₆ alkyl optionally substituted with optionally substituted heterocyclyl, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 23. The compound according to any one of claims 1 to 22, wherein R ⁴ is heterocyclyl optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 23. A compound according to any one of claims 1 to 22, wherein R ⁴ is aryl optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, optionally substituted heterocyclyl, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 23. The compound according to any one of claims 1 to 22, wherein R ⁴ is heteroaryl optionally substituted by one or more groups selected from the group consisting of halogen, hydroxyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted C ₁ -C ₆ thioalkoxy, and optionally substituted heterocyclyl, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 23. A compound according to any one of claims 1 to 22, wherein R ⁴ is hydrogen, methyl, ethyl,



and
A compound selected from the group consisting of or a pharmaceutically acceptable salt, solvate or isotope derivative thereof. 29. The compound according to any one of claims 1 to 28, wherein R ⁵ is hydrogen, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 23. The compound according to any one of claims 1 to 22, wherein R ⁴ and R ⁵ together with the nitrogen to which they are attached form an optionally substituted heterocyclyl, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. A compound selected from the compounds of Table 1 below:














or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof: A compound selected from the compounds of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. A pharmaceutical composition comprising the compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. A combination comprising the compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, and a second prophylactic or therapeutic agent. 33. A compound according to any one of claims 1 to 32 for use in the treatment and/or prevention of a proliferative disorder such as cancer or tumor in a subject. 36. The compound of claim 35, wherein the proliferative disorder or cancer is selected from the group consisting of malignant and benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, hepatocarcinoma, sarcoma, glioblastoma, head and neck cancer, melanoma, and other hyperplastic conditions such as benign hyperplasia of the skin and benign hyperplasia of the prostate. A method of treating and/or preventing a proliferative disorder such as cancer or a tumor in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of claim 33, or a combination of claim 34. 38. The method of claim 37, wherein the proliferative disorder or cancer is selected from the group consisting of malignant and benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, hepatocarcinoma, sarcoma, glioblastoma, head and neck cancer, melanoma, and other hyperplastic conditions such as benign hyperplasia of the skin and benign hyperplasia of the prostate. Use of a compound according to any one of claims 1 to 32 for use in the manufacture of a medicament. MAPK, PDGFR, Src, PAKs and -Kit, EphA2, EphB4, FGFR, Axl, and c-Met as a method for producing an anti-proliferative effect in a subject having a proliferative disorder, cancer or tumor sensitive to inhibition of one or more kinases selected from the group consisting of -Kit, EphA2, EphB4, FGFR, Axl, and c-Met, wherein an effective amount of the compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of claim 33, or the combination of claim 34 is administered to the subject. A method comprising administering. A compound according to any one of claims 1 to 32 for use in the treatment of neurodegenerative diseases. 42. The compound according to claim 41, wherein the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease and Huntington's disease. A method of treating a neurodegenerative disease in a subject comprising administering to the subject an effective amount of a compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of claim 33, or a combination of claim 34. 44. The method of claim 43, wherein the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease and Huntington's disease. A method of inhibiting the activity of one or more kinases selected from the group consisting of MAPK, PDGFR, Src, PAKs, c-Kit, EphA2, EphB4, FGFR, Axl, and c-Met, comprising contacting a cell with an effective amount of a compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of claim 33, or a combination of claim 34, wherein the contacting is performed in vitro, ex vivo, or in vivo. How it is done within.